Leukemia, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome
Conditions
Brief summary
The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity conditioning (Clo/BU4 regimen) prior to transplant and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for stem cell transplant in the treatment of aggressive hematologic malignancies in subjects where more conventional approaches are failing.
Detailed description
Transplants with stem cells collected from the blood of an unrelated donor (allo-HSCT) are being used more commonly for many blood cancers which are not curable with more conventional methods of chemotherapy. Although allo-HSCT has great potential, there are still high risks due to infections, graft-versus-host disease (GVHD), where the donor's cells attack the recipient's tissues as foreign, and due to toxic effects of the chemotherapy drugs given to prepare (or condition) the recipient's bone marrow for transplant. As a reduced intensity conditioning, a combination of Fludarabine and a lower dose of Busulfan (Flu/BU2) is one of the most popular regimens. Among full-intensity regimens, a combination of Fludarabine and standard-dose Busulfan (Flu/BU4) has been investigated recently and shown to be very well tolerated. Clofarabine, similar to Fludarabine, is known to have a stronger anti-tumor effect than Fludarabine and has shown promise in treating aggressive acute leukemias. In addition, evidence is that it is well-tolerated with manageable side effects especially in older subjects. Thus replacing Fludarabine with Clofarabine in a full-intensity transplant regimen, Clo/BU4 may provide a regimen with increased anti-tumor activity without adding significant risks of toxicity. The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity regimen (Clo/BU4) and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for HSCT in the treatment for aggressive hematologic malignancies, in subjects where more conventional approaches are failing.
Interventions
Clofarabine IV (dose levels) * 1st dose level: 20 mg/m2/day x 5 days * 2nd dose level: 30 mg/m2/day x 5 days * 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days
Peripheral blood stem cell transplant, after pre-conditioning drug treatment
RADIATIONTotal Lymphoid Irradiation
Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant
Sponsors
Genzyme, a Sanofi Company
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
Disease Criteria * Acute leukemia or chronic myelogenous leukemia in blastic crisis or accelerated phase, not in remission at the time of transplant * Myelodysplastic syndrome, with more than 5% blasts in bone marrow at the time of transplant * Hodgkin and Non-Hodgkin Lymphomas: Not in CR in PET scan or CT scan before transplant, or relapsed within 1 year from previous remission * CLL not in remission * Multiple Myeloma, not in remission * Suitable donor available (related or unrelated) Age, Organ Function Criteria * Age: ≤ 70 years * Cardiac: LV Ejection Fraction ≥ 40% by MUGA or Echocardiogram * Pulmonary: FEV1 and FVC ≥ 40% predicted, and DLCO (corrected for hemoglobin) ≥ 40% of predicted * Renal: Adult population: serum creatinine ≤ 1.0 mg/dL (if serum creatinine \> 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be \> 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation) * Renal: Pediatric population: serum creatinine clearance ≥ 90 ml/min/1.73 m2 as calculated by the Schwartz formula for estimated GFR * Hepatic: serum total bilirubin ≤ 2.0 mg/dl and AST / ALT ≤ ULN x 4 * Performance status: Karnofsky ≥ 70%
Exclusion criteria
* Other active life-threatening cancer requiring treatment other than allo-HSCT * HIV1 or HIV2 positive * Uncontrolled medical or psychiatric disorder * Uncontrolled viral or fungal infection * Active CNS leukemia * Non-compliant to medications * No appropriate caregivers identified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regimen Related Toxicities | two years | The incidence of non-hematological toxicities (Common Terminology Criteria for Adverse Events (CTCAE) 3.0) from initiation of conditioning to Day + 30 or toxicities after day +30, possibly, probably or definitely related to conditioning for all patients treated with Clofarabine (independent of dose level). |
| One-year Overall Survival Rate for AML | 1 year | Percent Overall Survival (OS) for at one year for subjects with Acute Myeloid Leukemia (AML). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Two-year Overall Survival for All Cases. | 2 years | Percent Overall Survival (OS) at two years for all patients. |
| Five Year Overall Survival for All Cases | five years | The number of patients alive at 5 years |
Countries
United States
Participant flow
Recruitment details
Patients with relapsed or refractory hematologic malignancies not in remission received unmanipulated HSCT with CloBu4 conditioning from October 2007 to November 2009 at the University of Michigan. Patients received a clofarabine dose of 20mg/m\^2, 30 mg/m\^2 or 40 mg/m\^2.
Participants by arm
| Arm | Count |
|---|---|
| Clo/BU4 20mg/m^2 Clofarabine/Busulfan x 4 : Clofarabine IV 20 mg/m\^2/day x 5 days
Busulfan IV 3.2 mg/kg daily x 4 days
Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment. | 6 |
| Clo/BU4 30mg/m^2 Clofarabine/Busulfan x 4 : Clofarabine IV 30 mg/m\^2/day x 5 days
Busulfan IV 3.2 mg/kg daily x 4 days
Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment. | 21 |
| Clo/BU4 40mg/m^2 Clofarabine/Busulfan x 4 : Clofarabine IV 40 mg/m\^2/day x 5 days
Busulfan IV 3.2 mg/kg daily x 4 days
Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment. | 19 |
| Total | 46 |
Baseline characteristics
| Characteristic | Total | Clo/BU4 40mg/m^2 | Clo/BU4 30mg/m^2 | Clo/BU4 20mg/m^2 |
|---|---|---|---|---|
| Age, Continuous | 53 years | 51 years | 54 years | 48.5 years |
| Disease Acute Lymphoblastic Leukemia (ALL) | 4 participants | 2 participants | 1 participants | 1 participants |
| Disease Acute Myeloid Leukemia (AML) | 31 participants | 14 participants | 13 participants | 4 participants |
| Disease Chronic Lymphocytic Leukemia (CLL) | 4 participants | 1 participants | 3 participants | 0 participants |
| Disease Chronic Myeloid Leukemia (CML) | 2 participants | 0 participants | 1 participants | 1 participants |
| Disease Multiple Myeloma (MM) | 1 participants | 0 participants | 1 participants | 0 participants |
| Disease Myelodysplastic Syndromes (MDS) | 1 participants | 1 participants | 0 participants | 0 participants |
| Disease Non-Hodgkin Lymphoma (NHL) | 3 participants | 1 participants | 2 participants | 0 participants |
| Region of Enrollment United States | 46 participants | 19 participants | 21 participants | 6 participants |
| Sex: Female, Male Female | 22 Participants | 11 Participants | 9 Participants | 2 Participants |
| Sex: Female, Male Male | 24 Participants | 8 Participants | 12 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 23 / 46 |
Outcome results
Primary
One-year Overall Survival Rate for AML
Percent Overall Survival (OS) for at one year for subjects with Acute Myeloid Leukemia (AML).
Time frame: 1 year
Population: Patients with Acute Myeloid Leukemia (AML)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clo/Bu4 | One-year Overall Survival Rate for AML | 48 percent overall survival |
Primary
Regimen Related Toxicities
The incidence of non-hematological toxicities (Common Terminology Criteria for Adverse Events (CTCAE) 3.0) from initiation of conditioning to Day + 30 or toxicities after day +30, possibly, probably or definitely related to conditioning for all patients treated with Clofarabine (independent of dose level).
Time frame: two years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clo/Bu4 | Regimen Related Toxicities | Liver | 56 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Gastrointestinal | 70 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Genito-Urinary | 4 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Cardiopulmonary | 10 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Neurologic | 8 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Skin | 11 toxicities |
| Clo/Bu4 | Regimen Related Toxicities | Other | 3 toxicities |
Secondary
Five Year Overall Survival for All Cases
The number of patients alive at 5 years
Time frame: five years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clo/Bu4 | Five Year Overall Survival for All Cases | 6 Participants |
Secondary
Two-year Overall Survival for All Cases.
Percent Overall Survival (OS) at two years for all patients.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clo/Bu4 | Two-year Overall Survival for All Cases. | 28 percent overall survival |