Acute Myeloid Leukemia, Leukemia Lymphoblastic, Acute, Neoplasm Recurrent
Conditions
Keywords
ALL, AML, Recurrence, Relapsed, Stem Cell Transplant, Non-myeloablative
Brief summary
Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include 1) patients with pre-existing health issues and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem cell transplant; and 3) leukemia patients with advanced disease who have been heavily pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with total body irradiation that can achieve durable donor engraftment without causing excessive toxicity.
Detailed description
Standard non-myeloablative regimens use Fludarabine and low dose total body irradiation (TBI) as pioneered by the Seattle group. Fludarabine is mainly used for its immuno-suppressive properties and has limited anti-leukemic effects. Since, the non-myeloablative and RIC regimens do not include intensive chemotherapy; relapse rates can be higher in RIC regimens compared to full myeloablative regimens. One way to improve overall survival in non-myeloablative / RIC setting is to add more effective anti-leukemia agents to prevent post-transplant relapses, without increasing TRM. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. Combining Clofarabine with low dose TBI as a non-myeloablative preparative regimen may improve overall outcomes of SCT in advanced hematological malignancies. Therefore, in this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with 2Gy TBI that can achieve durable donor engraftment without causing excessive toxicity. The MFD determined from this pilot will be used in the next phase to study the outcomes after using this combination for SCT in this very high risk population.
Interventions
DRUGClofarabine
Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry (30, 40 or 52 mg/m2).
RADIATIONTotal Body Irradiation
Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day 0 according to institutional guidelines.
OTHERStem Cell Transplantation
Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.
DRUGCyclosporine
Cyclosporine is given IV based on body weight at: * Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs). * Age \> 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs) Cyclosporine should be started on day -1 after completion of Clofarabine. Levels should be maintained between 300-400 ng/ml.
DRUGMycophenolate Mofetil
MMF will be at 15 mg/kg, based on adjusted body weight, q 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant. Oral doses will be rounded to the nearest 250 mg (capsules are 250 mg). MMF is also available in oral suspension form. MMF will be given until day +40 post transplant and then tapered by 10% per week to be discontinued by day +90.
Sponsors
Genzyme, a Sanofi Company
Therapeutic Advances in Childhood Leukemia Consortium
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
Since this is a Phase 1 study, any patient who is a candidate for a non-myeloablative SCT because he/she cannot tolerate the standard myeloablative preparative therapy is eligible for this trial. Briefly, the following groups of patients will be targeted and are eligible for this trial: * Patients with presence of organ system dysfunction or severe systemic infections that significantly increase the risk of TRM with standard myeloablative regimens. * History of previous myeloablative allogeneic or autologous transplantation. * Heavily pre-treated leukemia patients, eg. Patients in CR after failure of ≥2 prior regimens.(eg. ALL CR ≥ 3). * Combination of toxicities or co-morbidities that leads the investigator to feel that the child is at high risk (\>50%) of TRM with standard ablative regimens. The eligibility criteria listed below are interpreted literally and cannot be waived. 1. Age: Patients must be \>1 and \< 21 years of age at the of study entry. 2. Diagnosis 1. Patients must have a diagnosis of ALL or AML. * ALL patients must be in clinical remission defined as BM morphology \<5% blasts and CNS 1 status. * AML patients must be in M1 (\<5% blasts) or M2 (\<20% blasts) marrow status with CNS 1 status. 2. Patient must have an ANC \> 750/ul. 3. Donor Selection: Patient must have one of the appropriate donor types as described below: 1. HLA identical sibling donor. 2. Complete matched unrelated donor, (matched at A, B, C, DR B1 and DQ, B1 at the allelic level based on high resolution typing for Class I and II antigens, 10/10 match). 3. 1 allelic mis-matched unrelated donor (antigen mis-matches are not allowed). 4. Stem Cell Source: The stem cell source from the donor must be one of the following: 1. Bone Marrow or Peripheral blood stem cells (PBSC) from a matched related donor. 2. PBSC from an unrelated donor. (Bone marrow is not acceptable for unrelated donors) 5. Performance Level: Karnofsky \> 50% for patients \> 10 years of age and Lansky \> 50% for patients \< 10 years of age. 6. Reproductive Function 1. Female patients of childbearing potential must have a negative serum pregnancy test confirmed within 2 weeks prior to enrollment. 2. Female patients with infants must agree not to breastfeed their infants while on this study. 3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study. 7. Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as indicated by the following laboratory values: 1. Patients must have a calculated creatinine clearance ≥ 70mL/min/m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k \* Height (cm)/serum creatinine (mg/dl). K is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys. 2. Total serum bilirubin \< 2 mg/dL. 3. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 × ULN. 8. Cardiac Function: Patient must have a shortening fraction (SF) \> 25%. If the SF is \<25%, patient must have an ejection fraction (EF) by MUGA of \>30%. 3.3.9 Pulmonary Function Patient must have pulmonary function as defined below: 1. DLCO \>30% 2. FVC/TLC \>30% 3. FEV1 \> 30% of predicted 4. Patient is not on continuous oxygen If patient is not old enough or unable to comply with pulmonary function tests, they must have a pulse ox \>92% in room air and not be on continuous oxygen. 9. Patients with prior exposure to Clofarabine are eligible. 10. Informed Consent: Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible. 11. Protocol Approval: All institutional, FDA, and OHRP requirements for human studies must be met.
Exclusion criteria
Patients will be excluded if they meet any of the following criteria: 1. Infection 1. Patients will be excluded if they have evidence of an active, progressive invasive infection. All patients with existing infections at the time study entry should be discussed with the study chair. * Patients may have stable invasive infections and still be eligible. * Patients with infections that are responsive to medical or surgical treatment as shown by radiographic and or microbial assessment may still be eligible. 2. Patients will be excluded if they have an active, uncontrolled systemic fungal, bacterial, viral or other infection. All patients with existing infections at the time of study entry should be discussed with the study chair. * An active uncontrolled infection is defined as exhibiting ongoing signs and symptoms related to the infection (fevers, positive blood cultures, chills, tachycardia, etc) despite appropriate antibiotics or other treatment. 2. Patient has a diagnosis of CML or MDS. 3. Patient has CNS 2 or CNS 3 status. 4. Patient is HIV positive. 5. Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. 6. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry. 7. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney (including dialysis patients), liver, or other organ system that may place the patient at undue risk to undergo treatment. 8. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). 9. Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Feasible Dose of Clofarabine | Day +100 | The primary objective of the study is to determine the maximum feasible dose (MFD) of Clofarabine that can be given in combination with 2Gy total body irradiation as a non-myeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients with relapsed leukemia. The MFD is defined as the highest clofarabine dose associated with both an acceptably low toxicity and low non-engraftment (NE) rate. NE is defined as \< 5% donor T cells at any time point during serial monitoring. Monitoring during the evaluation period is required Day +30, +60 and +100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) | Days +30, 60, 100, 180 | Donor engraftment will be assessed by serial monitoring of T-cell (CD3) and myeloid (CD33) chimerism at day +30, 60, 100, 180 and 1 year at the local institution using PCR based VNTR/STR amplification techniques. Neutrophil engraftment is defined as first day of an ANC ≥500/μL on 3 consecutive measurements. |
| Transplant Related Mortality (TRM) at Day +100 | Day 100 | TRM is defined as any mortality within the first 100 days post stem cell infusion associated with regimen related toxicity, infection, or GVHD. |
| Days to Platelet Recovery | Days +30, 60, 100, 180 | Platelet recovery is defined as the first day of 3 consecutive measurements of platelets ≥20,000/μL after at least 7 days without transfusion support. |
Countries
United States
Participant flow
Pre-assignment details
At each dose level, after the first 3 patients or after 6 patients, the dose level will be either escalated to the next dose level, expanded, or de-escalated, or the study will be halted, depending on the number of observed Transplant Related Mortality (TRM) or Severe Renal Insufficiency (SRI) and Non-engraftment (NE) and evaluation status of surrounding dose levels.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A- Related Donor- Dose Level 1 Dose Level 1 Clofarabine 40 mg/m\^2. Cohort A will include patients who have matched related donors. | 3 |
| Cohort B- Related Donor - Dose Level 2 Dose Level 2 Clofarabine 52 mg/m\^2. Cohort B will include patients who have matched related donors. | 6 |
| Cohort C- Unrelated Donor - Dose Level 1 Dose Level 1 Clofarabine 40 mg/m\^2. Cohort C will include patients who have matched unrelated donors. | 3 |
| Cohort D- Unrelated Donor - Dose Level 2 Dose Level 2 Clofarabine 52 mg/m\^2. Cohort D will include patients who have matched unrelated donors. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Cohort A- Related Donor- Dose Level 1 | Cohort B- Related Donor - Dose Level 2 | Cohort C- Unrelated Donor - Dose Level 1 | Cohort D- Unrelated Donor - Dose Level 2 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 15 years | 5.5 years | 3.5 years | 9 years | 14.5 years |
| CD34+ cell dose | 6.8 million cells per kg | 6.8 million cells per kg | 6.8 million cells per kg | 6.8 million cells per kg | 6.8 million cells per kg |
| Diagnosis Acute Lymphoblastic Leukemia (ALL) | 2 Participants | 4 Participants | 2 Participants | 3 Participants | 11 Participants |
| Diagnosis Acute Myeloid Leukemia (AML) | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 7 Participants |
| Donor type Related Donor | 3 Participants | 6 Participants | 0 Participants | 0 Participants | 9 Participants |
| Donor type Unrelated Donor | 0 Participants | 0 Participants | 3 Participants | 6 Participants | 9 Participants |
| Performance Status 50-80 | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Performance Status 80-90 | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
| Performance Status 90-100 | 1 Participants | 4 Participants | 3 Participants | 5 Participants | 13 Participants |
| Prior liver transplantation | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
| Prior myeloablative allogeneic HSCT | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 1 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 8 Participants |
| Stem cell source Bone Marrow | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Stem cell source Peripheral Blood | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 15 Participants |
| Trisomy 21 | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 5 / 12 |
| other Total, other adverse events | 6 / 6 | 10 / 12 |
| serious Total, serious adverse events | 1 / 6 | 0 / 12 |
Outcome results
Primary
Maximum Feasible Dose of Clofarabine
The primary objective of the study is to determine the maximum feasible dose (MFD) of Clofarabine that can be given in combination with 2Gy total body irradiation as a non-myeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients with relapsed leukemia. The MFD is defined as the highest clofarabine dose associated with both an acceptably low toxicity and low non-engraftment (NE) rate. NE is defined as \< 5% donor T cells at any time point during serial monitoring. Monitoring during the evaluation period is required Day +30, +60 and +100.
Time frame: Day +100
Population: This analysis was performed for the entire study population. Cohorts were not separately analyzed for the maximum feasible dose of clofarabine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entire Study Population | Maximum Feasible Dose of Clofarabine | 52 mg/m^2 |
Secondary
Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD)
Donor engraftment will be assessed by serial monitoring of T-cell (CD3) and myeloid (CD33) chimerism at day +30, 60, 100, 180 and 1 year at the local institution using PCR based VNTR/STR amplification techniques. Neutrophil engraftment is defined as first day of an ANC ≥500/μL on 3 consecutive measurements.
Time frame: Days +30, 60, 100, 180
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Entire Study Population | Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) | 20 Days |
| Cohort B- Related Donor- Dose Level 2 | Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) | 19.5 Days |
| Cohort C- Unrelated Donor- Dose Level 1 | Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) | 19 Days |
| Cohort D- Unrelated Donor- Dose Level 2 | Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) | 15.5 Days |
Secondary
Days to Platelet Recovery
Platelet recovery is defined as the first day of 3 consecutive measurements of platelets ≥20,000/μL after at least 7 days without transfusion support.
Time frame: Days +30, 60, 100, 180
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Entire Study Population | Days to Platelet Recovery | 10 Days |
| Cohort B- Related Donor- Dose Level 2 | Days to Platelet Recovery | 13.5 Days |
| Cohort C- Unrelated Donor- Dose Level 1 | Days to Platelet Recovery | 11 Days |
| Cohort D- Unrelated Donor- Dose Level 2 | Days to Platelet Recovery | 10.5 Days |
Secondary
Transplant Related Mortality (TRM) at Day +100
TRM is defined as any mortality within the first 100 days post stem cell infusion associated with regimen related toxicity, infection, or GVHD.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Entire Study Population | Transplant Related Mortality (TRM) at Day +100 | 0 Participants |
| Cohort B- Related Donor- Dose Level 2 | Transplant Related Mortality (TRM) at Day +100 | 0 Participants |
| Cohort C- Unrelated Donor- Dose Level 1 | Transplant Related Mortality (TRM) at Day +100 | 0 Participants |
| Cohort D- Unrelated Donor- Dose Level 2 | Transplant Related Mortality (TRM) at Day +100 | 0 Participants |
Post Hoc
CD3 Donor Chimerism at Day 30 (Full Donor)
Donor engraftment was assessed by testing of chimerism in the T cell (CD3) subpopulation at day +30 done by local institution using PCR-based analyses of polymorphic microsatellite regions.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Entire Study Population | CD3 Donor Chimerism at Day 30 (Full Donor) | 2 Participants |
| Cohort B- Related Donor- Dose Level 2 | CD3 Donor Chimerism at Day 30 (Full Donor) | 4 Participants |
| Cohort C- Unrelated Donor- Dose Level 1 | CD3 Donor Chimerism at Day 30 (Full Donor) | 3 Participants |
| Cohort D- Unrelated Donor- Dose Level 2 | CD3 Donor Chimerism at Day 30 (Full Donor) | 6 Participants |
Post Hoc
CD3 Donor Chimerism at Day 30 (Mixed Chimerism)
Donor engraftment was assessed by testing of chimerism in the T cell (CD3) subpopulation at day +30 done by local institution using PCR-based analyses of polymorphic microsatellite regions.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Entire Study Population | CD3 Donor Chimerism at Day 30 (Mixed Chimerism) | 1 Participants |
| Cohort B- Related Donor- Dose Level 2 | CD3 Donor Chimerism at Day 30 (Mixed Chimerism) | 1 Participants |
| Cohort C- Unrelated Donor- Dose Level 1 | CD3 Donor Chimerism at Day 30 (Mixed Chimerism) | 0 Participants |
| Cohort D- Unrelated Donor- Dose Level 2 | CD3 Donor Chimerism at Day 30 (Mixed Chimerism) | 0 Participants |
Post Hoc
Number of Participants With Acute GVHD ≥ Grade 2
Acute GVHD was graded according to consensus grading criteria (Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825-828.)
Time frame: Within 100 Days Post-SCT (Stem Cell Transplant)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Entire Study Population | Number of Participants With Acute GVHD ≥ Grade 2 | 1 Participants |
| Cohort B- Related Donor- Dose Level 2 | Number of Participants With Acute GVHD ≥ Grade 2 | 3 Participants |
| Cohort C- Unrelated Donor- Dose Level 1 | Number of Participants With Acute GVHD ≥ Grade 2 | 1 Participants |
| Cohort D- Unrelated Donor- Dose Level 2 | Number of Participants With Acute GVHD ≥ Grade 2 | 3 Participants |