Phase I/II Trial of Fludarabine Plus Busulfan and Allogeneic Progenitor Cell Support
Study Details
Study Description
Brief Summary
Objectives:
-
To determine the relative toxicities, engraftment potential, kinetics of engraftment, degree of chimerism and disease control achieved with the combination of fludarabine and busulfan at different dose levels and different dose schedules in patients undergoing allogeneic stem cell transplant (SCT).
-
Determine pharmacokinetics, and toxicity of intravenous busulfan given at equal total dose levels given four times daily, or once daily.
-
In vivo determination of fludarabine inhibitory effects on DNA repair.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
Treatment: Participants will have blood tests and bone marrow tests as well as tests to check lung, heart, kidney, and liver functions. Participants will receive busulfan by vein for 2 to 4 days depending on their age and medical condition. All participants will receive fludarabine which will be given over 4 days. Participants undergoing unmatched or matched unrelated donors will receive ATG over 4 days to help with the engraftment of the donor progenitor cells. All drugs are given through the vein daily.
The donor blood cells will be taken from the donor through a process known as apheresis. This will occur after the donor has received 2 days of granulocyte colony stimulating factor (G-CSF) to increase her/his white cell count. The G-CSF will also increase the number of very immature (stem cells) that are to be collected. Apheresis is similar to a platelet donation, but white cells and stem cells are collected instead. About 3 to 5 apheresis procedures will be needed to get enough cells for infusion. If apheresis is not used, donor bone marrow will be taken under general anesthesia.
After the participants receives the donor stem cells, the stem cells divide and reconstitute bone marrow function, blood function, and immunity. The donor stem cells are given after the chemotherapy to shorten the period of low blood counts. They are also given at this time to achieve an antileukemic effect whereby the donor immune cells will recognize the participant's leukemia as "foreign" and prevent its recurrence. A small amount of donor cells will be kept for infusion on a future date (usually 3 and 6 months post transplant) to try to prevent the disease from coming back.
During the 4 to 8 weeks following blood cell infusion, participants will need frequent blood tests to monitor their counts and blood chemistries. Participants will need frequent blood transfusion 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 check response. Participants that achieve normal bone marrow and blood counts will be evaluated to determine the most appropriate form of future therapy. Participants who fail to respond to treatment will be offered other therapies.
This is an investigational study. All through all drugs are commercially available. Up to 140 participants will take part in this study. All will be enrolled at UT MD Anderson Cancer Center.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Busulfan + Fludarabine Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. |
Drug: Busulfan
Starting Dose 0.8 mg/kg by vein every 6 hours x 12 doses.
Other Names:
Drug: Fludarabine
30 mg/m^2 by vein daily x 4 days.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) [1 month]
Continual reassessment method (four times a day) used to determine an MTD, with a target toxicity probability of 20%, where "toxicity" is defined as grade 3 or 4 conventional toxicity [National Cancer Institute Common Toxicity Criteria (NCI-CTC)]. Participant evaluation in a cohort with each modality is 30 days.
Secondary Outcome Measures
- Number of Participants With Graft Versus Host Disease (GVHD) [5 years]
Tacrolimus and Methotrexate used for acute graft versus host disease (aGVHD) prophylaxis, clinical grading AGVHD criteria (Days 1-100): Grade 1: + to ++ skin rash; no gut involvement; no decrease in clinical performance status; Grade 2: + to +++ skin rash; + gut involvement and/or + liver involvement; mild decrease in performance status; Grade 3: ++ to +++ skin rash; ++ to +++ gut involvement and/or ++ to ++++ liver involvement; marked decrease in performance status; Grade 4: Similar to Grade 3 with ++ to ++++ organ involvement and extreme decrease in performance status.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Less than physiologic 75 years of age.
-
Interferon resistant late chronic phase CML not eligible for a protocol of higher priority.
-
Accelerated/Blastic Phase CML.
-
Acute leukemia or Intermediate to High Risk MDS according to the IPPS.
-
Any Lymphoma or Myeloma beyond CR1 ineligible for a protocol of higher priority.
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Patients must have an HLA compatible donor willing to donate either peripheral blood or bone marrow progenitor cells.
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Both patients and donor must sign written informed consents.
Exclusion Criteria:
-
Uncontrolled infection
-
Bilirubin >3.0
-
Creatinine >2.5
-
Performance Status >Zubrod 2
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
Investigators
- Principal Investigator: Richard E. Champlin, MD, BS, UT MD Anderson Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- DM99-251
Study Results
Participant Flow
| Recruitment Details | Recruitment period: November 2003 to August 2011. All recruitment was done at UT MD Anderson Cancer Center. |
|---|---|
| Pre-assignment Detail | Of the 82 participants enrolled, two (2) participants were excluded from the trial before starting treatment. |
| Arm/Group Title | Busulfan + Fludarabine |
|---|---|
| Arm/Group Description | Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. |
| Period Title: Overall Study | |
| STARTED | 80 |
| COMPLETED | 80 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Busulfan + Fludarabine |
|---|---|
| Arm/Group Description | Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. |
| Overall Participants | 80 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
56
|
| Sex: Female, Male (Count of Participants) | |
| Female |
26
32.5%
|
| Male |
54
67.5%
|
| Region of Enrollment (participants) [Number] | |
| United States |
80
100%
|
Outcome Measures
| Title | Maximum Tolerated Dose (MTD) |
|---|---|
| Description | Continual reassessment method (four times a day) used to determine an MTD, with a target toxicity probability of 20%, where "toxicity" is defined as grade 3 or 4 conventional toxicity [National Cancer Institute Common Toxicity Criteria (NCI-CTC)]. Participant evaluation in a cohort with each modality is 30 days. |
| Time Frame | 1 month |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was per protocol. |
| Arm/Group Title | Busulfan + Fludarabine |
|---|---|
| Arm/Group Description | Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. |
| Measure Participants | 80 |
| Number [mg/kg] |
11.2
|
| Title | Number of Participants With Graft Versus Host Disease (GVHD) |
|---|---|
| Description | Tacrolimus and Methotrexate used for acute graft versus host disease (aGVHD) prophylaxis, clinical grading AGVHD criteria (Days 1-100): Grade 1: + to ++ skin rash; no gut involvement; no decrease in clinical performance status; Grade 2: + to +++ skin rash; + gut involvement and/or + liver involvement; mild decrease in performance status; Grade 3: ++ to +++ skin rash; ++ to +++ gut involvement and/or ++ to ++++ liver involvement; marked decrease in performance status; Grade 4: Similar to Grade 3 with ++ to ++++ organ involvement and extreme decrease in performance status. |
| Time Frame | 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was per protocol for 73 patients out of 80 patients due to 3 early deaths and 4 non engraftments. |
| Arm/Group Title | Tacrolimus + Methotrexate |
|---|---|
| Arm/Group Description | Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. |
| Measure Participants | 73 |
| Grade 2 |
18
22.5%
|
| Grade 3-4 |
8
10%
|
Adverse Events
| Time Frame | March 2000 to December 2004 (4 years, 8 months) | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Busulfan + Fludarabine | |
| Arm/Group Description | Busulfan starting 0.8 mg/kg by vein (IV) every 6 hours for 12 doses; Fludarabine 30 mg/m^2 IV daily for 4 days. | |
All Cause Mortality |
||
| Busulfan + Fludarabine | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Busulfan + Fludarabine | ||
| Affected / at Risk (%) | # Events | |
| Total | 72/80 (90%) | |
| Blood and lymphatic system disorders | ||
| Graft failure | 2/80 (2.5%) | |
| Gastrointestinal disorders | ||
| Mucositis | 1/80 (1.3%) | |
| Epistaxis | 3/80 (3.8%) | |
| General disorders | ||
| Death | 8/80 (10%) | |
| Chronic Graft versus Host Disease | 8/73 (11%) | |
| Acute Graft versus Host Disease | 26/73 (35.6%) | |
| Hepatobiliary disorders | ||
| Elevated alanine aminotransferase | 1/80 (1.3%) | |
| Infections and infestations | ||
| Infections | 12/80 (15%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Diffuse alveolar haemorrhage | 1/80 (1.3%) | |
| Pneumonia | 7/80 (8.8%) | |
| Shortness of breath | 3/80 (3.8%) | |
Other (Not Including Serious) Adverse Events |
||
| Busulfan + Fludarabine | ||
| Affected / at Risk (%) | # Events | |
| Total | 80/80 (100%) | |
| Eye disorders | ||
| Occular | 5/80 (6.3%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 30/80 (37.5%) | |
| Nausea | 39/80 (48.8%) | |
| Vomiting | 6/80 (7.5%) | |
| Stomatitis/Esophagitis | 23/80 (28.8%) | |
| General disorders | ||
| Fever | 5/80 (6.3%) | |
| Lethargy | 3/80 (3.8%) | |
| Hepatobiliary disorders | ||
| Elevated alkaline phosphate | 3/80 (3.8%) | |
| Hepatotoxicity | 15/80 (18.8%) | |
| Elevated alanine aminotransferase | 27/80 (33.8%) | |
| Nervous system disorders | ||
| Altered mental status | 2/80 (2.5%) | |
| Renal and urinary disorders | ||
| Elevated Creatinine | 32/80 (40%) | |
| Hemorrhagic cystitis | 2/80 (2.5%) | |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Richard E. Champlin/Professor |
|---|---|
| Organization | UT MD Anderson Cancer Center |
| Phone | |
| ytdinh@mdanderson.org |
- DM99-251