Leukemia
Conditions
Keywords
recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia
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).
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.
Interventions
DRUGcyclophosphamide
Given IV
DRUGetoposide
Given IV
PROCEDUREallogeneic bone marrow transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
PROCEDUREallogeneic hematopoietic stem cell transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
PROCEDUREperipheral blood stem cell transplantation
Occurs approximately 48 hours after completion of cyclophosphamide
RADIATIONintensity-modulated radiation therapy
Undergo IMRT
RADIATIONtomotherapy
Undergo IMRT using helical tomotherapy
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to 55 Years
Healthy volunteers
No
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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
STUDY_CHAIRAnthony S. Stein, MD
City of Hope Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Level 1: 1200cGy 150cGy BID x Days 1-4. Total dose 1200cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 3 |
| Level 2: 1350cGy 150cGy BID Day 1-4 then 150 cGy QD Day 5. Total dose 1350cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 3 |
| Level 3: 1500cGy Limited Dose to Ribs, Sternum, Liver, Brain 1200cGy 150cGy BID Day 1-5. Total dose 1500cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 9 |
| Level 4: 1500cGy Limited Dose to Liver, Brain 1200cGy 150cGy BID Day 1-5. Total dose 1500cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Level 5: 1600cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy 160cGy BID Day 1-5. Total dose 1600cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Level 6: 1700cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy 170cGy BID Day 1-5. Total dose 1700cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Level 7: 1800cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy 180cGy BID Day 1-5. Total dose 1800cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Level 8: 1900cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy 190cGy BID Day 1-5. Total dose 1900cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Level 9: 2000cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy 200cGy BID Day 1-5. Total dose 2000cGy.
cyclophosphamide: Given IV
etoposide: Given IV
allogeneic bone marrow transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
allogeneic hematopoietic stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
peripheral blood stem cell transplantation: Occurs approximately 48 hours after completion of cyclophosphamide
intensity-modulated radiation therapy: Undergo IMRT
tomotherapy: Undergo IMRT using helical tomotherapy | 6 |
| Total | 51 |
Baseline characteristics
| Characteristic | Total | Level 9: 2000cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy | Level 8: 1900cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy | Level 7: 1800cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy | Level 6: 1700cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy | Level 5: 1600cGy Limited Dose to Liver, Porta-hepatic, Brain 1200cGy | Level 4: 1500cGy Limited Dose to Liver, Brain 1200cGy | Level 3: 1500cGy Limited Dose to Ribs, Sternum, Liver, Brain 1200cGy | Level 2: 1350cGy | Level 1: 1200cGy |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 34.4 years | 39.4 years | 38.4 years | 36.5 years | 52.5 years | 37.5 years | 31.1 years | 32.7 years | 24.5 years | 34.4 years |
| Race/Ethnicity, Customized Asian or Pacific Islander | 10 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black, not of Hispanic origin | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 17 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other, Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 22 Participants | 2 Participants | 1 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 51 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 9 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 31 Participants | 4 Participants | 5 Participants | 5 Participants | 2 Participants | 3 Participants | 3 Participants | 7 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 20 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 9 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 9 / 9 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 9 | 3 / 6 | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 | 1 / 6 |
Outcome results
Primary
Maximum Tolerated Dose of Intensity-modulated Radiotherapy (Phase I)
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.
Time frame: 30 days post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Levels: 1200 cGy to 2000cGy | Maximum Tolerated Dose of Intensity-modulated Radiotherapy (Phase I) | 2000 cGy |