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Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer

Primary Purpose

Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
busulfan
etoposide
intensity-modulated radiation therapy
allogeneic hematopoietic stem cell transplantation
allogeneic bone marrow transplantation
peripheral blood stem cell transplantation
tomotherapy
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia in Remission

Eligibility Criteria

6 Years - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion

  • Patients with the following diagnoses are eligible for this study: Advanced myeloid malignancy with a disease status of more than second remission, induction failure, or relapse; Chronic myeloid leukemia in blast crisis; Myelodysplasia, specifically refractory anemia with excess blasts (RAEB)
  • All candidates for this study must have a HLA (-A, -B, -C, -DR) identical sibling who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele-matched unrelated donor or minor mismatches as per BMT SOP that allows Tacrolimus and Sirolimus to be given for GVH prophylaxis; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange)
  • Prior therapy with VP-16, busulfan, hydrea and gleevec are allowed
  • A cardiac evaluation with electrocardiogram and MUGA or echocardiogram is required for all patients; patients must have an ejection fracture of greater than or equal to 50%
  • Patients must have a serum creatinine of less than or equal to 1.2 or creatinine clearance > 80 ml/min
  • A bilirubin of less than or equal to 1.5; patients should also have an SGOT and SGPT less than 5 times the upper limit of normal
  • Pulmonary function tests including DLCO will be performed; FEV1 and DLCO should be greater than 50% of predicted normal value
  • Time from the end of last induction or reinduction attempt should be greater than or equal to 21 days
  • A signed (IRB approved) informed consent document is required; the patient, donor family member, and transplant team (physician, nurse, and social worker) meet together at least once prior to starting the transplant procedure to review all pertinent risk/benefit information as part of the consenting process; alternative treatment modalities are also discussed at this meeting

Exclusion

  • Prior radiation therapy/exposure that prevents patient from receiving IMRT (Determination will be made by the Radiation Oncologist)
  • Patients who have previously undergone a blood/marrow transplant and now have relapsed disease
  • Patients with a psychological or medical condition that the treating physician deems unacceptable to proceed to allogeneic bone marrow transplant
  • Pregnancy
  • EKG showing ischemic changes or abnormal rhythm and echocardiogram showing ejection fraction < 50 % or abnormal wall motion

Sites / Locations

  • City of Hope

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I: 1200cGy

Arm II: 1350cGy

Arm Description

1200cGy = 150cGy x 8 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive GVHD prophylaxis that excludes methotrexate.

1350cGy = 150cGy x 9 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Intensity-modulated Radiation Therapy (Phase I)
The highest dose tested in which fewer than 33% of patients experienced DLT attributable to the study treatment when at least six patients were treated at the dose and are evaluable for toxicity. The MDT is one dose level below the DLT level. At least six patients will be treated at the MTD.

Secondary Outcome Measures

Full Information

First Posted
October 5, 2007
Last Updated
March 28, 2022
Sponsor
City of Hope Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT00540995
Brief Title
Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer
Official Title
Phase I/II Study of Intravenous (IV) Busulfan and Etoposide (VP-16) Combined With Escalated Doses of Large Field Image-Guided Intensity Modulated Radiation Therapy (IMRT) Using Helical Tomotherapy as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients With Advanced Myeloid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
Unable to safely escalate to TMLI doses that were hypothesized to be effective and less toxic than FTBI. Likely due to the giving of Busulfan prior to radiation delivery. Therefore, the study was abandoned and no further patients were accrued.
Study Start Date
June 11, 2007 (Actual)
Primary Completion Date
May 17, 2011 (Actual)
Study Completion Date
August 9, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Giving chemotherapy drugs, such as busulfan and etoposide, and intensity-modulated radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving intensity-modulated radiation therapy together with busulfan and etoposide before a transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects and best dose of intensity-modulated radiation therapy when given together with busulfan and etoposide followed by a donor stem cell transplant and to see how well it works in treating patients with advanced myeloid cancer.
Detailed Description
OBJECTIVES: I. To establish the maximum tolerated dose (MTD) of a large field image-guided IMRT, using helical tomotherapy, when given in combination with IV busulfan and VP-16 as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical sibling in patients with advanced myeloid malignancies. (Phase I) II. To describe the toxicities at each dose level studied. (Phase I) III. To estimate the radiation doses to the whole body, normal organs, and bone marrow through serial imaging studies following the administration of IMRT. (Phase I) IV. To estimate the overall survival probability, disease-free survival probability, and relapse rate associated with this preparative regimen. (Phase II) V. To characterize the treatment related mortality and toxicity profile (early/late) associated with this regimen. (Phase II) VI. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population conditioned with whole-body radiotherapy. (Phase II) OUTLINE: This is a phase I, dose-escalation study of intensity-modulated radiation therapy followed by a phase II study. PREPARATIVE CHEMOTHERAPY: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive GVHD prophylaxis that excludes methotrexate. After completion of study treatment, patients are followed periodically for 1 year and then annually for 2 years thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I: 1200cGy
Arm Type
Experimental
Arm Description
1200cGy = 150cGy x 8 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive GVHD prophylaxis that excludes methotrexate.
Arm Title
Arm II: 1350cGy
Arm Type
Experimental
Arm Description
1350cGy = 150cGy x 9 doses: Patients receive busulfan IV once daily over 2 hours on days -15 and -13 and then every 6 hours on days -12 to -9. Patients also receive etoposide IV on day -3. Patients undergo image-guided intensity-modulated radiation therapy using helical tomotherapy on days -8 to -5.
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon, Myelosan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, epipodophyllotoxin, VePesid, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
intensity-modulated radiation therapy
Other Intervention Name(s)
IMRT
Intervention Description
Initially 150 cGy X 8 doses with gradual dose escalation to 200 cGy X 10 doses
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Stem cell transplantation occurs on Day 0 after High Dose Therapy
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow transplantation
Other Intervention Name(s)
bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow
Intervention Description
Stem cell transplantation occurs on Day 0 after High Dose Therapy
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Stem cell transplantation occurs on Day 0 after High Dose Therapy
Intervention Type
Radiation
Intervention Name(s)
tomotherapy
Other Intervention Name(s)
helical tomotherapy
Intervention Description
Initially 150 cGy X 8 doses with gradual dose escalation to 200 cGy X 10 doses
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of Intensity-modulated Radiation Therapy (Phase I)
Description
The highest dose tested in which fewer than 33% of patients experienced DLT attributable to the study treatment when at least six patients were treated at the dose and are evaluable for toxicity. The MDT is one dose level below the DLT level. At least six patients will be treated at the MTD.
Time Frame
from initial treatment date to Day 30 post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Patients with the following diagnoses are eligible for this study: Advanced myeloid malignancy with a disease status of more than second remission, induction failure, or relapse; Chronic myeloid leukemia in blast crisis; Myelodysplasia, specifically refractory anemia with excess blasts (RAEB) All candidates for this study must have a HLA (-A, -B, -C, -DR) identical sibling who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele-matched unrelated donor or minor mismatches as per BMT SOP that allows Tacrolimus and Sirolimus to be given for GVH prophylaxis; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange) Prior therapy with VP-16, busulfan, hydrea and gleevec are allowed A cardiac evaluation with electrocardiogram and MUGA or echocardiogram is required for all patients; patients must have an ejection fracture of greater than or equal to 50% Patients must have a serum creatinine of less than or equal to 1.2 or creatinine clearance > 80 ml/min A bilirubin of less than or equal to 1.5; patients should also have an SGOT and SGPT less than 5 times the upper limit of normal Pulmonary function tests including DLCO will be performed; FEV1 and DLCO should be greater than 50% of predicted normal value Time from the end of last induction or reinduction attempt should be greater than or equal to 21 days A signed (IRB approved) informed consent document is required; the patient, donor family member, and transplant team (physician, nurse, and social worker) meet together at least once prior to starting the transplant procedure to review all pertinent risk/benefit information as part of the consenting process; alternative treatment modalities are also discussed at this meeting Exclusion Prior radiation therapy/exposure that prevents patient from receiving IMRT (Determination will be made by the Radiation Oncologist) Patients who have previously undergone a blood/marrow transplant and now have relapsed disease Patients with a psychological or medical condition that the treating physician deems unacceptable to proceed to allogeneic bone marrow transplant Pregnancy EKG showing ischemic changes or abnormal rhythm and echocardiogram showing ejection fraction < 50 % or abnormal wall motion
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anthony Stein
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Terminated study

Learn more about this trial

Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer

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