Acute Myeloid Leukemia, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, 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), Adult Acute Promyelocytic Leukemia (M3), Recurrent Adult Acute Myeloid Leukemia
Conditions
Brief summary
RATIONALE: Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Colony stimulating factors, such as G-CSF, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine to see how well it works when given together with cytarabine and G-CSF in treating patients with relapsed or refractory acute myeloid leukemia
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of clofarabine, and the dose-limiting toxicities of the combination of clofarabine and cytarabine with G-CSF priming, in the treatment of patients with relapsed or refractory AML. SECONDARY OBJECTIVES: I. To determine the hematological and non-hematological side effect profile of the combination of clofarabine, cytarabine, and G-CSF. II. To determine the efficacy of clofarabine in combination with cytarabine and G-CSF priming in the treatment of patients with relapsed or refractory AML. III. To determine the disease-free and overall survival after therapy with clofarabine, cytarabine, and G-CSF for relapsed or refractory AML. OUTLINE: This is a dose escalation study of clofarabine. PART I: INDUCTION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine IV over 2 hours on days 1-5, and filgrastim (G-CSF) subcutaneously once daily beginning 24 hours prior to chemotherapy and continuing until blood count recover. Patients with residual leukemia (\>= 5% blasts by morphology) at day 14 and if blast remain \> 5% by day 21 receive a second course of induction therapy. CONSOLIDATION THERAPY: Patients receive clofarabine, cytarabine, and G-CSF as in induction therapy. Patients may receive a second course of consolidation therapy depending on response and whether additional therapy (e.g., stem cell transplant or donor lymphocyte infusion) is planned. PARTS II and III: Patients receive induction therapy and consolidation therapy as in part 1. After completion of study treatment, patients are followed every 3 months for 2 years and then annually for 3 years.
Interventions
DRUGclofarabine
Given IV
DRUGcytarabine
Given IV
BIOLOGICALfilgrastim
Given subcutaneously
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* ECOG performance status 0-2 * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent * Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment * Male and female patients must be willing to use an effective contraceptive method during the study and for a minimum of 6 months after study treatment * Serum Total or Direct bilirubin =\< 1.5 times upper limit of normal (ULN) * Aspartate transaminase (AST)/alanine transaminase (ALT) =\< 2.5 times ULN * Diagnosis of acute myeloid leukemia by WHO criteria, either relapsed or refractory; acute promyelocytic leukemia \[acute promyelocytic leukemia with t(15;17)(q22;q12) and variants\] would be eligible only after failure of a regimen containing arsenic trioxide * 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 m\^2 * Alkaline phosphatase =\< 2.5 times ULN
Exclusion criteria
* Use of investigational agents within 30 days or initiation of any other anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea, and intrathecal therapy for leukemic meningitis * 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) * Pregnant or lactating patients * Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results * Have any other severe concurrent disease, history of serious organ dysfunction, or disease involving the heart, kidney, liver (including symptomatic hepatitis, veno-occlusive disease, or hepatic graft-versus-host disease \[for acute \>= grade 2\]), or other organ system dysfunction * No concomitant cytotoxic therapy or investigational therapy is allowed during the study with the exception of intrathecal therapy for leukemic meningitis; intrathecal therapy must not be given during or within 24 hours of any 5 day Clofarabine/Cytarabine treatment period * To the extent possible, use of nephrotoxic (e.g., vancomycin, amphotericin B, etc) and hepatotoxic (e.g., voriconazole, cyclosporine, etc) agents is to be avoided during clofarabine; use of alternative medications (e.g., herbal or botanical for anticancer purposes) is not permitted during the entire study period * Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol * More than two failed induction attempts for initial diagnosis or current relapse; for patients enrolled under part III of the protocol, patients must be at first salvage after relapse less than one year from complete remission, or salvage after initial induction chemotherapy * Allogeneic transplant recipients on immunosuppression or on treatment for GVHD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rates by Salvage Number | 45 days after the last dose of clofarabine | Number of participants in each Salvage number category who achieved a Complete Remission. Salvage number refers to whether treatment with GCLAC on this study was the pariticipant's first salvage regimen (1), second salvage regimen (2), or third or greater salvage regimen (3 or greater). |
| Dose-limiting Toxicity as Assessed by NCI CTCAE v3.0 | 45 days after the last dose of clofarabine | — |
| Response Rates by Cytogenetic Risk Category | 45 days after the last dose of clofarabine | Number of participants who achieved Complete Remission (less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) under each cytogenetic risk category. |
| Response Rates by Cytogenetic Risk Category and Clofarabine Dose | 45 days after the last dose of clofarabine | Number of participants under each Cytogenetic Risk Category and Clofarabine dose who achieve CR (Complete Remission = less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) or CRp (Complete Remission, but with a platelet count of less than 100,000/microL). |
| Response Rates by Duration First Complete Remission (CR1) | 45 days after the last dose of clofarabine | Number of participants whose first Complete Remission lasted 0, 1-6, 6-12, or greater than 12 months. Only those participant who had a first CR are included in this data. |
| Maximum Tolerated Dose of Clofarabine | 45 days after the last dose of clofarabine | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy | At five years after the last dose of clofarabine | Number of Patients Surviving at Five Years |
| Disease-free Survival | At five years after the last dose of clofarabine | Number of participants who survived and were disease-free at 5 years |
| Overall Survival | At five years after the last dose of clofarabine | — |
| Hematologic and Non-hematologic Side Effect Profile | 45 days after the last dose of clofarabine | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I See Detailed Description
clofarabine: Given IV
cytarabine: Given IV
filgrastim: Given subcutaneously | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Continuous | 53 years |
| AML Onset: de novo | 32 Participants |
| AML Onset: secondary | 18 Participants |
| Favorable cytogenetics (at initial diagnosis) | 3 Participants |
| First salvage | 32 Participants |
| Intermediate cytogenetics (at initial diagnosis) | 27 Participants |
| Median first CR duration | 26 weeks |
| Refractory | 18 Participants |
| Relapsed | 32 Participants |
| Second or greater salvage | 18 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 36 Participants |
| Unfavorable cytogenetics (at initial diagnosis) | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 23 / 50 |
Outcome results
Primary
Dose-limiting Toxicity as Assessed by NCI CTCAE v3.0
Time frame: 45 days after the last dose of clofarabine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Dose-limiting Toxicity as Assessed by NCI CTCAE v3.0 | 2 Participants |
Primary
Maximum Tolerated Dose of Clofarabine
Time frame: 45 days after the last dose of clofarabine
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Maximum Tolerated Dose of Clofarabine | 25 mg/m^2 of clofarabine |
Primary
Response Rates by Cytogenetic Risk Category
Number of participants who achieved Complete Remission (less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) under each cytogenetic risk category.
Time frame: 45 days after the last dose of clofarabine
Population: Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category | Favorable risk Complete Remission | 3 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category | Intermediate risk Complete remission | 10 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category | Unfavorable risk Complete remission | 9 Participants |
Primary
Response Rates by Cytogenetic Risk Category and Clofarabine Dose
Number of participants under each Cytogenetic Risk Category and Clofarabine dose who achieve CR (Complete Remission = less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) or CRp (Complete Remission, but with a platelet count of less than 100,000/microL).
Time frame: 45 days after the last dose of clofarabine
Population: Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Favorable Risk + 25 mg/m^2 achieve CR | 2 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Intermediate Risk + 15 mg/m^2 achieve CR | 2 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Intermediate Risk + 20 mg/m^2 achieve CR | 3 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Intermediate Risk + 25 mg/m^2 achieve CR | 5 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Intermediate Risk + 25 mg/m^2 achieve CRp | 4 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Unfavorable Risk + 15 mg/m^2 achieve CR | 2 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Unfavorable Risk + 20 mg/m^2 achieve CR | 1 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Unfavorable Risk + 25 mg/m^2 achieve CR | 6 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Cytogenetic Risk Category and Clofarabine Dose | Unfavorable Risk + 25 mg/mg^2 achieve CRp | 3 Participants |
Primary
Response Rates by Duration First Complete Remission (CR1)
Number of participants whose first Complete Remission lasted 0, 1-6, 6-12, or greater than 12 months. Only those participant who had a first CR are included in this data.
Time frame: 45 days after the last dose of clofarabine
Population: Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Duration First Complete Remission (CR1) | Duration CR1 (months): greater than 12 | 3 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Duration First Complete Remission (CR1) | Duration CR1 (months): 0 | 12 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Duration First Complete Remission (CR1) | Duration CR1 (months): 1-6 | 4 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Duration First Complete Remission (CR1) | Duration CR1 (months): 6-12 | 2 Participants |
Primary
Response Rates by Salvage Number
Number of participants in each Salvage number category who achieved a Complete Remission. Salvage number refers to whether treatment with GCLAC on this study was the pariticipant's first salvage regimen (1), second salvage regimen (2), or third or greater salvage regimen (3 or greater).
Time frame: 45 days after the last dose of clofarabine
Population: Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Salvage Number | Salvage number 1 | 16 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Salvage Number | Salvage number 2 | 5 Participants |
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Response Rates by Salvage Number | Salvage number 3 or greater | 0 Participants |
Secondary
Disease-free Survival
Number of participants who survived and were disease-free at 5 years
Time frame: At five years after the last dose of clofarabine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Disease-free Survival | 11 Participants |
Secondary
Efficacy
Number of Patients Surviving at Five Years
Time frame: At five years after the last dose of clofarabine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Efficacy | 12 Participants |
Secondary
Hematologic and Non-hematologic Side Effect Profile
Time frame: 45 days after the last dose of clofarabine
Population: Data not collected
Secondary
Overall Survival
Time frame: At five years after the last dose of clofarabine
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC) | Overall Survival | 9 months |