Imatinib Mesylate, Busulfan, Fludarabine, and Antithymocyte Globulin for CML Patients

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00499889
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 42
• Location: 1
• Arm: 1
• Duration (Months): 81
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Primary Objective:

To estimate the probability of molecular complete remission at one year for the described sequential treatment approach, with nonablative hematopoietic transplantation, post transplant imatinib mesylate and donor lymphocyte infusion, in patients with Ph-positive Chronic Myelogenous Leukemia (CML) not in blastic transformation.

Secondary Objective:

Response to post transplant Imatinib mesylate therapy for 12 weeks as treatment of residual disease, response to donor lymphocyte infusion (DLI) for residual disease following imatinib mesylate therapy, as well as engraftment, toxicity, disease free survival and survival, effect of busulfan pharmacokinetics on study outcome.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Imatinib Mesylate; Drug: Fludarabine (Fludara); Drug: Busulfan; Drug: Antithymocyte Globulin (ATG); Drug: Tacrolimus; Drug: Methotrexate; Procedure: Donor lymphocyte infusion (DLI); Procedure: Stem Cell Transplant	Phase 2

Detailed Description

Patients will have blood and bone marrow tests performed as well as chest and sinus X-rays and tests of their heart and lung function. Approximately 5 tablespoons of blood will be drawn.

All patients in this study will receive imatinib mesylate by mouth for 9 days, unless the patient is known to be allergic or have symptomatic intolerance to the drug, or if the leukemia has failed to respond to imatinib. Fludarabine 40 mg/m2 by vein for 4 days (days -5 to -2), busulfan 130 mg/m2 by vein for 2 days (days -3 and -2), and ATG (Antithymocyte Globulin) 2.5 mg/kg by vein for 3 days (-3,-2 and -1).

Patients will then receive the donor bone marrow or blood stem cells by vein over approximately one hour on day 0.

After the infusion of the donor cells, you will receive immunosuppressive therapy with tacrolimus and methotrexate to decrease the risk of developing graft-vs-host disease (GvHD).

Patients will need frequent blood tests to monitor their counts and blood chemistries. This is generally done daily while in hospital and at least twice per week for the first 100 days post transplant. You may need frequent blood transfusions and may have to be admitted to the hospital to receive antibiotics if they develop fever. Bone marrow will be examined frequently beginning four weeks after treatment to evaluate response to treatment; Blood and bone marrow exams are to be performed at one, two three, six, 12 and 18 months post transplant and yearly thereafter for 5 years. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle.

Patients in whom treatment produces a remission, in which no sign of the leukemia can be detected, will receive no further therapy unless the leukemia recurs. Patients with evidence of leukemia after 3 months from the transplant will receive additional treatment with imatinib mesylate; those with detectable leukemia after an additional 3 months may receive an infusion of immune cells from the transplant donor.

If there is evidence of leukemia after the transplant, you will receive additional treatment with imatinib mesylate. If leukemia cells can still be detected, additional donor immune cells will be given to you by vein.

Patients are considered on the study for 5 years after the transplant.

A total of 90 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Imatinib Mesylate, Busulfan, Fludarabine, Antithymocyte Globulin and Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia
• Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Imatinib, Busulfan, Fludara + Antithymocyte Globulin Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.

Drug: Imatinib Mesylate; 400 mg by mouth twice daily for 9 Days; Other Names: Gleevec STI571 ; Drug: Fludarabine (Fludara); 40 mg/m^2 by vein daily for 4 Days; Other Names: Fludarabine Phosphate Fludara Fludarabine ; Drug: Busulfan; 130 mg/m^2 by vein daily for 2 Days; Other Names: Busulfex Myleran ; Drug: Antithymocyte Globulin (ATG); 2.5 mg/kg by vein daily for 3 Days; Other Names: ATG Thymoglobulin ; Drug: Tacrolimus; Tacrolimus levels maintained between 5-15 ng/dl, first as continuous IV infusion, and converted to oral every 12 hour dosing as tolerated. Starting day -2 until day 180.; Other Names: Prograf ; Drug: Methotrexate; 5 mg/m2 on days 1, 3, 6 and 11.; Procedure: Donor lymphocyte infusion (DLI); Infusion of lymphocytes from the original bone marrow donor by vein if relapse after >4 weeks of imatinib.; Other Names: buffy coat fusion donor leukocyte infusion apheresis donor immune cell infusion ; Procedure: Stem Cell Transplant; Infusion of donor bone marrow or blood stem cells by vein over approximately one hour on day 0.; Other Names: stem cell infusion stem cell transplantation ALLOGENEIC STEM CELL TRANSPLANTATION HSCT hematopoietic stem cell transplant Bone Marrow transplant PBSC Peripheral Blood Stem Cell

Outcome Measures

Primary Outcome Measures

1. Number of Participants in Complete Molecular Remission at 1 Year [Baseline to 1 year]

   Participants at 1 year in molecular remission, post transplant, post imatinib mesylate and donor lymphocyte infusion (DLI). Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests (this test is most commonly used in clinical trials).

Secondary Outcome Measures

1. Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy [1 Year]

   Number of participants with response of molecular complete remission (mCR) to Imatinib Mesylate therapy as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.

2. Participants' With mCR Response to Post Transplant DLI [1 year]

   Number of participants with response of molecular complete remission (mCR) to DLI as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of Ph+ chronic myelogenous leukemia (CML) in first chronic phase without a complete hematologic response after 3 months of Imatinib mesylate therapy, or >=35% Ph+ cells despite > 6 months of Imatinib mesylate treatment, or after disease progression from a complete or partial response. Any patient with accelerated phase or blast crisis who achieves a subsequent chronic phase is eligible. Patients must have an HLA matched related or unrelated donor or one antigen mismatched related donor.

2. Patients should be less than 70 years of age. Patients less than 30 years of age who achieve a hematologic remission with imatinib therapy are eligible regardless of cytogenetic response.

3. Patients are stratified as Group 1: First chronic phase, Group 2 Accelerated phase or blast crisis that achieved a hematologic remission with imatinib mesylate-based treatment.

Exclusion Criteria:

1. Zubrod Performance Scale (PS) >=2, uncontrolled infection, Creatinine > 2.0 mg/dl; Ejection fraction < 40%; Carbon Monoxide Diffusing Capacity (DLCO) < 45% of predicted; Serum bilirubin > 2 gm/dl; GPT (Glutamic-pyruvic transaminase) or GOT (glutamic-oxaloacetic transaminase)> 3 times normal values. Patients should not be human immunodeficiency virus (HIV) seropositive or pregnant.

2. Patients should not have progressed to accelerated phase or blast crisis while receiving imatinib mesylate containing therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Richard E. Champlin, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The University of Texas M.D.Anderson Cancer Center

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00499889
• Other Study ID Numbers: ID02-901
• First Posted: Jul 12, 2007
• Last Update Posted: Apr 23, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by M.D. Anderson Cancer Center: Chronic Myelogenous Leukemia; Allogeneic Stem Cell Transplantation; Leukemia; Imatinib Mesylate; Gleevec; Busulfan; Busulfex; Myleran; Fludarabine; ATG; STI571; Antithymocyte Globulin; Thymoglobulin
• Additional relevant MeSH terms: Leukemia; Vidarabine; Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Imatinib Mesylate; Tacrolimus; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 02/12/03 to 01/15/09. All patients were recruited at UT MD Anderson Cancer Center.
Pre-assignment Detail	One patient registered for transplant became ineligible before any treatment due to infection and was taken off study; 41 patients received the transplant regimen and an Allogeneic transplant.

Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
Period Title: Overall Study
STARTED	42
COMPLETED	41
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
Overall Participants	42
Age (Count of Participants)
<=18 years	1 2.4%
Between 18 and 65 years	39 92.9%
>=65 years	2 4.8%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	42.2 (42)
Sex: Female, Male (Count of Participants)
Female	20 47.6%
Male	22 52.4%
Region of Enrollment (participants) [Number]
United States	42 100%

Outcome Measures

1. Secondary Outcome

Title	Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy
Description	Number of participants with response of molecular complete remission (mCR) to Imatinib Mesylate therapy as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

Analysis was per protocol. Only 19 participants having the post transplant Imatinib Mesylate Therapy out of the 41 participants treated were analyzed for this outcome.

Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
Measure Participants	19
Number [Participants]	10 23.8%

2. Primary Outcome

Title	Number of Participants in Complete Molecular Remission at 1 Year
Description	Participants at 1 year in molecular remission, post transplant, post imatinib mesylate and donor lymphocyte infusion (DLI). Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests (this test is most commonly used in clinical trials).
Time Frame	Baseline to 1 year

Outcome Measure Data

Analysis Population Description

Analysis was per protocol. One patient did not receive treatment and was excluded from analysis.

Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
Measure Participants	41
Number [participants]	21 50%

3. Secondary Outcome

Title	Participants' With mCR Response to Post Transplant DLI
Description	Number of participants with response of molecular complete remission (mCR) to DLI as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Only 8 participants having the post-transplant DLI out of the 41 participants treated were analyzed for this outcome.

Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
Measure Participants	8
Number [Participants]	4 9.5%

Adverse Events

Time Frame	5 years and 6 months
Arm/Group Title	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
Arm/Group Description	Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.
All Cause Mortality
	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
	Affected / at Risk (%)	# Events
Total	12/41 (29.3%)
Blood and lymphatic system disorders
severe anemia	1/41 (2.4%)	1
Thrombocytopenia	1/41 (2.4%)	1
Myelosupression	1/41 (2.4%)	1
Cardiac disorders
Hypertensive Crisis	1/41 (2.4%)	1
Gastrointestinal disorders
Abdominal Distention	1/41 (2.4%)	1
Hepatobiliary disorders
increased bilirubin	1/41 (2.4%)	1
Immune system disorders
GVHD	2/41 (4.9%)	2
Infections and infestations
Neutropenic Fever	2/41 (4.9%)	2
Nervous system disorders
neurologic	1/41 (2.4%)	1
Skin and subcutaneous tissue disorders
Urticaria	1/41 (2.4%)	1
Other (Not Including Serious) Adverse Events
	Mesylate, Busulfan, Fludarabine + Antithymocyte Globulin
	Affected / at Risk (%)	# Events
Total	37/41 (90.2%)
Blood and lymphatic system disorders
Granulocytes	1/41 (2.4%)	1
platelets	1/41 (2.4%)	1
increased prothrombin time	1/41 (2.4%)	1
Cardiac disorders
increased blood pressure	1/41 (2.4%)	1
Gastrointestinal disorders
Gastrointestional Disorder (other)	2/41 (4.9%)	2
esophagitis	4/41 (9.8%)	4
nausea	4/41 (9.8%)	4
diarrhea	1/41 (2.4%)	1
General disorders
fatigue	1/41 (2.4%)	1
Hepatobiliary disorders
increased alanine aminotransferase (ALT)	1/41 (2.4%)	1
increased LDH	1/41 (2.4%)	1
Infections and infestations
fever	4/41 (9.8%)	4
infection	6/41 (14.6%)	6
decreased neutrpoenia	1/41 (2.4%)	1
Nervous system disorders
neurolgic other	2/41 (4.9%)	2
headache	1/41 (2.4%)	1
drowiness	1/41 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
shortness of breath	1/41 (2.4%)	1
pneumonia	1/41 (2.4%)	1
Skin and subcutaneous tissue disorders
skin other	1/41 (2.4%)	1
skin rash	5/41 (12.2%)	5

Limitations/Caveats

Study completed early due to support issues.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.