Busulfan and Fludarabine in Patients With AML and MDS

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00502905
• Collaborator: (none)
• Enrollment: 200
• Location: 1
• Arm: 1
• Duration (Months): 61
• Patients Per Site Per Month: 3.3

Study Details

Study Description

Brief Summary

Primary Objectives:

1. To administer multiple doses of an intravenous formulation of busulfan (Bu) at a dose adjusted to yield a blood drug level with a median daily area under the plasma concentration curve (AUC) of approximately 6,500 µMol-min. This dose will be given intravenously over three hours once daily for four (4) days, in combination with Fludarabine at a dose of 40 mg/m2 as preparation for bone marrow or peripheral stern cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes.

2. To determine the outcome of Acute Myeloid Leukemia (AML)/myelodysplastic syndromes (MDS) patients undergoing treatment with this regimen. Data regarding engraftment, toxicity, relapse rate, long-term (disease-free) outcome, and overall survival will be collected.

3. To determine the safety profile of this regimen when utilized as preparation for allogeneic transplantation.

4. To describe the plasma pharmacokinetics of busulfan when administered intravenously in this regimen.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Busulfan; Drug: Fludarabine	Phase 2

Detailed Description

Patients who agree to the optional pharmacology procedures #1 will initially receive a therapeutic test dose of busulfan to test the blood levels over time; this information will be used to determine the subsequent high-dose busulfan doses. Patients who do not agree to the optional pharmacology procedure will receive a fixed dose of busulfan as has previously been done for 3 years.

Patients in this study will then receive fludarabine through a central venous catheter over one hour, once a day, for four days. High-dose Busulfan will be injected through the catheter over three hours, once a day, for four days, starting immediately after fludarabine.

After two days of rest, the allogeneic bone marrow, peripheral blood stem cells or cord blood will then be given intravenously. Patients will receive the drug Granulocyte colony-stimulating factor (G-CSF - Neupogen) as an injection under the skin until their blood counts recover.

Patients will remain in the hospital for about 4-6 weeks. After discharge, patients will continue as outpatients in the hospital area until they are able to safely leave the immediate hospital area or for a minimum of 100 days after the transplant. Some patients may need to receive spinal taps with instillation of cytosine arabinoside and hydrocortisone several times over the year after transplantation. This is only for patients with a previous clinical history of leukemic involvement of the brain.

This is an investigational study. The FDA has approved the study drugs. Up to 200 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of High-Dose Intravenous Busulfan and Fludarabine With Allogeneic Marrow and Peripheral Blood Progenitor Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
• Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Busulfan + Fludarabine Once a day for four days, Busulfan 130 mg/m^2 through intravenous catheter over 3 hours immediately after Fludarabine 40 mg/m^2 over 1 hour.	Drug: Busulfan; 130 mg/m^2 injected through the intravenous catheter over three hours, once a day, for four days, starting immediately after Fludarabine.; Other Names: Busulfex Myleran ; Drug: Fludarabine; 40 mg/m^2 through a central venous catheter over one hour, once a day, for four days.; Other Names: Fludarabine Phosphate Fludara

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Successful Engraftment [Study period one week prior to transplant through post Day 28]

   Successful Engraftment defined as first of 3 consecutive days with Absolute neutrophil count (ANC) equal to or more than 0.5 * 10^9/L. Failure to engraft by day +30 considered primary engraftment failure. Study period one week prior to transplant through post Day 28.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 66 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Acute leukemia past first remission, in first or subsequent relapse, in first remission (high-risk, i.e., cytogenetics other than t(8;21, inv 16, t(15;17)) or induction failures.

2. Myelodysplastic syndromes in any clinical stage, excluding only patients who have isolated stable mono-cytopenia and who are clinically stable.

3. Patient has not been administered any other systemic chemotherapeutic drug (including Mylotarg) within 21 days prior to trial enrollment (BMT Day -7 or BMT day -9). (Hydroxyurea and intrathecal chemotherapy is permitted).

4. No uncontrolled infection.

5. Patients up to age 65 will be eligible for this study.

6. ALLOGENEIC TRANSPLANTATION:

Patients should have an acceptable related or unrelated volunteer donor available for a bone marrow peripheral blood progenitor cell or cord blood transplant. Bone marrow and peripheral blood cell donors should be matched for at least 5 of 6 HLA A, B and DR loci. Cord blood donors should be matched for at least 4 of 6 A, B and DR loci.

1. Life expectancy is not severely limited.

2. Pulmonary, cardio, renal and liver function tests normal.

3. In patients < 7 years pulmonary function will be assessed per pediatric BMT routine.

4. No evidence of chronic active hepatitis or cirrhosis.

5. HIV-negative.

6. Female patient is not pregnant

7. Signed informed consent.

8. Patient admitted on Sunday, or Monday to allow for pharmacokinetic directed therapy.

Exclusion Criteria:

1. Not fulfilling eligibility criteria above.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	U.T.M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UT MD Anderson Cancer Center website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00502905
• Other Study ID Numbers: ID01-011
• First Posted: Jul 18, 2007
• Last Update Posted: May 28, 2012
• Last Verified: May 1, 2012

• Keywords provided by M.D. Anderson Cancer Center: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Busulfan; Busulfex; Myleran; Fludarabine; Fludarabine Phosphate; Fludara
• Additional relevant MeSH terms: Leukemia; Vidarabine; Fludarabine; Fludarabine phosphate; Busulfan

Study Results

Participant Flow

Recruitment Details	Recruitment Period: April 12, 2001 through July 14, 2005. All participants recruited at UT MD Anderson Cancer Center.
Pre-assignment Detail	Of the 200 participants enrolled, four participants were excluded from the trial and did not receive treatment.

Arm/Group Title	Busulfan + Fludarabine
Arm/Group Description	Busulfan 130 mg/m^2 + Fludarabine 40 mg/m^2 given daily for four days
Period Title: Overall Study
STARTED	196
COMPLETED	196
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Busulfan + Fludarabine
Arm/Group Description	Busulfan 130 mg/m^2 + Fludarabine 40 mg/m^2 given daily for four days
Overall Participants	196
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43 (13)
Sex: Female, Male (Count of Participants)
Female	93 47.4%
Male	103 52.6%
Region of Enrollment (participants) [Number]
United States	196 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Successful Engraftment
Description	Successful Engraftment defined as first of 3 consecutive days with Absolute neutrophil count (ANC) equal to or more than 0.5 * 10^9/L. Failure to engraft by day +30 considered primary engraftment failure. Study period one week prior to transplant through post Day 28.
Time Frame	Study period one week prior to transplant through post Day 28

Outcome Measure Data

Analysis Population Description

Analysis per protocol.

Arm/Group Title	Busulfan + Fludarabine
Arm/Group Description	Busulfan 130 mg/m^2 + Fludarabine 40 mg/m^2 given daily for four days
Measure Participants	196
Number [participants]	192 98%

Adverse Events

Time Frame	7 years and 7 months
Arm/Group Title	Busulfan + Fludarabine
Arm/Group Description	Busulfan 130 mg/m^2 + Fludarabine 40 mg/m^2 given daily for four days
All Cause Mortality
	Busulfan + Fludarabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Busulfan + Fludarabine
	Affected / at Risk (%)	# Events
Total	68/196 (34.7%)
Blood and lymphatic system disorders
Thrombotic Thrombocytopenic Purpura	2/196 (1%)	2
Hemolytic Uremic Syndrome	1/196 (0.5%)	1
Cardiac disorders
Pericarditis	1/196 (0.5%)	1
Cardiac Failure	1/196 (0.5%)	1
Deep Vein Thrombosis	1/196 (0.5%)	1
Gastrointestinal disorders
Nausea	3/196 (1.5%)	3
Mucositis	2/196 (1%)	2
General disorders
Graft vs Host Disease	15/196 (7.7%)	15
Fever	3/196 (1.5%)	3
Plasmapheresis	1/196 (0.5%)	1
Death due to Relapse	2/196 (1%)	2
Ascites	1/196 (0.5%)	1
Graft Failure	3/196 (1.5%)	3
Hepatobiliary disorders
Elevated serum glutamic oxaloacetic transaminase (SGOT)	2/196 (1%)	2
Cholecystectomy	1/196 (0.5%)	1
Immune system disorders
Infection	2/196 (1%)	2
Nervous system disorders
Bell's Palsy	1/196 (0.5%)	1
Altered Mental Status	4/196 (2%)	4
Seizure	3/196 (1.5%)	3
Dizziness	1/196 (0.5%)	1
Renal and urinary disorders
Hemorrhagic Cystitis	7/196 (3.6%)	7
Hematuria	2/196 (1%)	2
Renal Failure	1/196 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolus	1/196 (0.5%)	1
Shortness of Breath	4/196 (2%)	4
Diffuse Alveolar Hemorrhage	2/196 (1%)	2
Pneumomediastinum	1/196 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Busulfan + Fludarabine
	Affected / at Risk (%)	# Events
Total	50/196 (25.5%)
Blood and lymphatic system disorders
Neutrophils/Granulocytes	2/196 (1%)	2
Cardiac disorders
Hypertension	1/196 (0.5%)	1
Eye disorders
Keratitis	1/196 (0.5%)	1
Gastrointestinal disorders
Diarrhea	1/196 (0.5%)	1
Gastrointestinal Hemorrhage	1/196 (0.5%)	1
Mucositis/Stomatitis	2/196 (1%)	2
Dysphagia	1/196 (0.5%)	1
Nausea	1/196 (0.5%)	1
Hepatobiliary disorders
Hyperbilirubinemia	3/196 (1.5%)	3
Increased Alanine transaminase (ALT)	5/196 (2.6%)	5
Veno-Occlusive Disease	2/196 (1%)	2
Immune system disorders
Allergy	1/196 (0.5%)	1
Infections and infestations
Infection	11/196 (5.6%)	11
Nervous system disorders
Altered Mental Status	2/196 (1%)	2
Seizure	1/196 (0.5%)	1
Renal and urinary disorders
Hematuria	2/196 (1%)	2
Cystitis	2/196 (1%)	2
Reproductive system and breast disorders
Vaginitis	1/196 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/196 (1%)	2
Pneumonitis	3/196 (1.5%)	3
Hemoptysis	1/196 (0.5%)	1
Skin and subcutaneous tissue disorders
Skin Rash	3/196 (1.5%)	3
Vascular disorders
Thrombosis/Thrombus	1/196 (0.5%)	1

Limitations/Caveats

[Not Specified]

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.