Clinical trial NCT00540995: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
First posted: 2007-10-08
Enrollment: 25
Sex: ALL
Minimum age (years): 6
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of Intensity-modulated Radiation Therapy (Phase I)
timeFrame: from initial treatment date to Day 30 post-transplant
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Anthony Stein
role: PRINCIPAL_INVESTIGATOR
References: