Intensity-Modulated Radiation Therapy, Etoposide, and Cyclophosphamide Followed By Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia
Study Details
Study Description
Brief Summary
RATIONALE: Giving intensity modulated radiation therapy (IMRT) and chemotherapy, such as etoposide and cyclophosphamide, 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 IMRT together with chemotherapy before 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 (IMRT) when given together with etoposide and cyclophosphamide followed by donor stem cell transplant and to see how well they work in treating patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
OBJECTIVES: I. To establish the maximum tolerated dose [MTD] of large field image-guided IMRT, using helical tomotherapy when given in combination with intravenous cyclophosphamide and VP-16 as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling or unrelated donor in patients with ALL or AML with induction failure or in relapse. (Phase I) II. To describe the toxicity at each dose level standard. (Phase I) III. To collect data on the radiation dose to normal organs and bone marrow using tomotherapy targeted total-body irradiation (TBI). (Phase I) IV. To estimate the overall survival probability, disease free survival probability and relapse rate associated with this 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 radiation. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of intensity-modulated radiation therapy (IMRT) followed by a phase II study.
PREPARATIVE REGIMEN: Patients undergo IMRT using helical tomotherapy once or twice daily on days -10 to -6 or -10 to -7. Patients also receive etoposide intravenously (IV) on day -6 or -5 and cyclophosphamide IV on day -4 or -3.
TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation on day -1 or day 0. After completion of study treatment, patients are followed up periodically for up to 2 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (radiation therapy, chemotherapy, transplant) PREPARATIVE REGIMEN: Patients undergo IMRT using helical tomotherapy once or twice daily on days -10 to -6 or -10 to -7. Patients also receive etoposide IV on day -6 or -5 and cyclophosphamide IV on day -4 or -3. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation on day -1 or day 0. |
Drug: cyclophosphamide
Given IV
Other Names:
Drug: etoposide
Given IV
Other Names:
Procedure: allogeneic bone marrow transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
Procedure: allogeneic hematopoietic stem cell transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
Procedure: peripheral blood stem cell transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
Radiation: intensity-modulated radiation therapy
Undergo IMRT
Other Names:
Radiation: tomotherapy
Undergo IMRT using helical tomotherapy
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose of intensity-modulated radiotherapy (Phase I) [30 days post transplant]
Toxicities will be recorded using two distinct grading systems: the modified Bearman scale and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 3.0 scale.
- Toxicity as assessed by NCI CTCAE v3.0 (Phase I) [Up to 2 years]
Toxicities observed at each dose level will be summarized in terms of type, severity, date of onset, duration, reversibility, and attribution. Tables will be created to summarize these toxicities and side effects by dose level.
- Overall survival (Phase II) [2 years post transplant]
Will be estimated using the product limit method of Kaplan-Meier and tested using the Log-Rank test. Confidence intervals will be estimated by calculating exact 95% confidence limits for a binomial parameter.
- Relapse-free survival (Phase II) [2 years post transplant]
Will be estimated using the product limit method of Kaplan-Meier and tested using the Log-Rank test. Confidence intervals will be estimated by calculating exact 95% confidence limits for a binomial parameter.
- Event-free survival (Phase II) [2 years post transplant]
Will be estimated using the product limit method of Kaplan-Meier and tested using the Log-Rank test. Confidence intervals will be estimated by calculating exact 95% confidence limits for a binomial parameter.
- Treatment-related mortality (Phase II) [2 years post transplant]
Will be estimated using the product limit method of Kaplan-Meier and tested using the Log-Rank test. Confidence intervals will be estimated by calculating exact 95% confidence limits for a binomial parameter.
- Relapse rate (Phase II) [2 years post transplant]
Will be estimated using the product limit method of Kaplan-Meier and tested using the Log-Rank test. Confidence intervals will be estimated by calculating exact 95% confidence limits for a binomial parameter.
- Fraction of patients experiencing 3-5 mucositis (Phase II) [Up to 2 years]
Secondary Outcome Measures
- Infection (Phase II) [2 years post transplant]
- Acute and chronic graft-versus-host disease (Phase II) [2 years post transplant]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with acute lymphocytic leukemia or acute myelogenous leukemia who are not in first or second remission (i.e., after failing remission induction therapy or in relapse or beyond second remission)
-
All candidates for this study must have a human leukocyte antigen (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; a single allele mismatch at A, B, C, DR, or DQ and a KIR mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques
-
Prior therapy with VP-16, Busulfan, and Cytoxan is allowed
-
A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of >= 50% established by multi gated acquisition scan (MUGA) or echocardiogram
-
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
-
Serum glutamic oxaloacetic transaminase (SGOT) less than 5 times the upper limit of normal
-
Serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal
-
Pulmonary functioning tests including diffusing capacity of carbon monoxide (DLCO) will be performed; forced expiratory volume in one second (FEV1) and DLCO should be greater than 50% of the predicted normal value
-
The time from the end last induction or reinduction attempt should be >= 14 days
-
Signed informed consent form approved by the Institutional Review Board (IRB) is required
DONOR: Any sibling donors who are histocompatible with the prospective recipient will be considered a suitable donor
-
Donors will be excluded if for psychological or medical reasons they are unable to tolerate the procedure
-
Donor should be able to donate peripheral blood stem cells or bone marrow
Exclusion Criteria:
-
Prior radiation therapy that would exclude the use of total-body irradiation
-
Patients who have undergone bone marrow transplantation previously and who have relapsed
-
Patients with psychological or medical condition that patients physician deems unacceptable to proceed to allogeneic bone marrow transplant
-
Pregnancy
-
Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010-3000 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Study Chair: Anthony S. Stein, MD, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 05021
- CHNMC-05021
- CDR0000579141
- NCI-2010-00427
- R01CA154491