Acute Myelogenous Leukemia, Acute Myeloid Leukemia
Conditions
Keywords
Acute myelogenous leukemia, Acute myeloid leukemia, newly Diagnosed AML, Clofarabine, CLASSIC II, CLO243
Brief summary
Clolar (clofarabine injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed acute lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens. This study will evaluate the efficacy of clofarabine in elderly patients with acute myelogenous leukemia (AML) who are unlikely to benefit from treatment with intensive chemotherapy regimens (cytarabine and anthracycline based regimens) used in younger patients with AML.
Interventions
DRUGclofarabine
Induction cycle 1: cycle 1 of clofarabine 30 mg/m\^2/day as a 1-hour intravenous infusion for 5 consecutive days. Reinduction (cycle 2) and/or Consolidation cycles (cycles 2-6): cycles repeated minimally every 28 days, of clofarabine 20 mg/m\^2/day as a 1-hour intravenous infusion for 5 consecutive days.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of AML (de novo, secondary or with an antecedent hematologic disorder \[AHD\]) * Age ≥ 60 years * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Presence of at least one adverse prognostic factor: Age ≥ 70 years; or AHD; or ECOG performance status of 2; or Intermediate or unfavorable (i.e., adverse) karyotype defined as any cytogenetic profile except the presence of any of the following: * t(8;21)(q22;q22) * inv(16)(p13;q22 or t(16;16)(p13;q22) * t(15;17)(q22;q12) and variants. * Adequate renal and hepatic function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; and 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 as calculated by the Modification of Diet in Renal Disease (MDRD) equation * Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 40% or left ventricular fractional shortening ≥ 22%
Exclusion criteria
* Diagnosis of acute promyelocytic leukemia * Prior treatment with clofarabine * Prior treatment for AML or an antecedent hematologic disorder * Prior hematopoietic stem cell transplant (HSCT) * Prior radiation therapy to the pelvis * Investigational agent received within 30 days prior to the first dose of study drug * Ongoing uncontrolled systemic infection * Diagnosis of another malignancy, unless the patient has been disease-free for at least 5 years following the completion of curative intent therapy with the following exceptions: Patients with treated non-melanoma skin cancer, in-situ carcinoma or cervical intraepithelial neoplasia regardless of disease-free duration are eligible for this study if definitive treatment for the condition has been completed; Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on PSA value are eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed * Clinical evidence of central nervous system (CNS) involvement * Severe concurrent medical condition or psychiatric disorder that would preclude study participation * Positive human immunodeficiency virus (HIV) test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | approximately Month 2 | Best response was assessed by the Independent Response Review Panel(IRRP) after two cycles of treatment. Overall remission(OR) is the sum of complete remission(CR) and complete remission in the absence of platelet recovery(CRp). CR includes normal values for peripheral blood cell counts (absolute neutrophil and platelet) and leukemic blast cells from bone marrow biopsy or aspirate, and absence of extramedullary disease. Partial remission(PR) includes recovery of peripheral blood cells with improved but still abnormal values in leukemic blast cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan Meier Estimate for Duration of Remission (DOR) | Up to 2 years | DOR was defined as the number of days from achievement of OR as assessed by the Independent Response Review Panel (IRRP) until IRRP-determined disease recurrence or death (any cause), plus 1 day. Participants who initiated alternative antileukemic treatment while in remission were censored on the date the therapy was initiated or on the date of last follow-up. |
| Kaplan Meier Estimate for Disease-free Survival (DFS) | Up to 2 years | DFS was defined as the number of days from achievement of IRRP-determined overall response until IRRP-determined disease recurrence or death (any cause), regardless of intervening alternative antileukemic treatment, plus 1 day. |
| Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Up to 2 years | Participants with AEs that occurred during the treatment and follow-up periods. AEs were classified according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. Treatment emergent is defined as any event that either first presents after baseline or worsens in severity after baseline. NCI Common Terminology Criteria for Severity: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5= Death related to AE |
| Percentage of Participants Who Died Within Thirty Days of Treatment (30-day Mortality Rate) | up to Day 30 | Percentage of participants who died within 30 days of the first dose of study drug, regardless of cause. |
| Kaplan Meier Estimates for Overall Survival (OS) | Up to 2 years | OS was defined as the number of days from first dose of clofarabine until death for all participants, plus 1 day. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | approximately Month 2 | The number of participants within each subgroup of baseline prognostic factors of the full analysis set who achieved a best response of either a complete response (CR) or a complete response in the absence of platelet recovery (CRp) as determined by the Independent Response Review Panel following a maximum of two cycles of treatment. |
Countries
United States
Participant flow
Pre-assignment details
129 patients were screened and 116 participants enrolled/treated at 20 sites.
Participants by arm
| Arm | Count |
|---|---|
| Clofarabine Participants received an induction cycle of clofarabine 30 mg/m\^2/day intravenous infusion for 5 consecutive days. Participants could then receive up to 5 additional cycles, repeated minimally every 28 days, of clofarabine 20 mg/m\^2/day intravenous infusion for 5 consecutive days. | 112 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Consent violation | 1 |
| Overall Study | Death | 16 |
| Overall Study | Disease recurrence | 10 |
| Overall Study | Failed independent confirmation of AML | 3 |
| Overall Study | Need for treatment prohibited by study | 1 |
| Overall Study | Other | 8 |
| Overall Study | Physician Decision | 19 |
| Overall Study | Treatment failure | 36 |
| Overall Study | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Clofarabine |
|---|---|
| Age at Enrollment < 70 years | 43 participants |
| Age at Enrollment >= 70 years | 69 participants |
| Age, Continuous | 71.4 years STANDARD_DEVIATION 5.92 |
| Antecedent Hematologic Disorder No | 67 participants |
| Antecedent Hematologic Disorder Not reported | 4 participants |
| Antecedent Hematologic Disorder Yes | 41 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 0 | 21 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 1 | 66 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 2 | 25 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 3 | 0 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 4 | 0 participants |
| Eastern Cooperative Oncology Group Performance Status ECOG 5 | 0 participants |
| Ethnicity Hispanic or Latino | 4 participants |
| Ethnicity Not Hispanic or Latino | 108 participants |
| Height | 166.50 cm STANDARD_DEVIATION 10.366 |
| Karyotype Favorable | 0 participants |
| Karyotype Intermediate | 46 participants |
| Karyotype Not reported | 4 participants |
| Karyotype Unfavorable | 62 participants |
| Participants Summarized by Number of Adverse Prognostic Factors 0 Adverse Prognostic Factors | 0 participants |
| Participants Summarized by Number of Adverse Prognostic Factors 1 Adverse Prognostic Factor | 25 participants |
| Participants Summarized by Number of Adverse Prognostic Factors 2 Adverse Prognostic Factors | 45 participants |
| Participants Summarized by Number of Adverse Prognostic Factors 3 Adverse Prognostic Factors | 40 participants |
| Participants Summarized by Number of Adverse Prognostic Factors 4 Adverse Prognostic Factors | 2 participants |
| Participants Summarized by Number of Adverse Prognostic Factors Excluding Intermediate Karyotype 0 Adverse Prognostic Factors | 7 participants |
| Participants Summarized by Number of Adverse Prognostic Factors Excluding Intermediate Karyotype 1 Adverse Prognostic Factor | 42 participants |
| Participants Summarized by Number of Adverse Prognostic Factors Excluding Intermediate Karyotype 2 Adverse Prognostic Factors | 35 participants |
| Participants Summarized by Number of Adverse Prognostic Factors Excluding Intermediate Karyotype 3 Adverse Prognostic Factors | 27 participants |
| Participants Summarized by Number of Adverse Prognostic Factors Excluding Intermediate Karyotype 4 Adverse Prognostic Factors | 1 participants |
| Race American Indian or Alaska Native | 1 participants |
| Race Asian | 4 participants |
| Race Black or African American | 7 participants |
| Race Native Hawaiian or Other Pacific Islander | 0 participants |
| Race Other | 2 participants |
| Race White | 98 participants |
| Secondary acute myeloid leukemia (AML) at baseline No | 101 participants |
| Secondary acute myeloid leukemia (AML) at baseline Yes | 11 participants |
| Sex: Female, Male Female | 60 Participants |
| Sex: Female, Male Male | 52 Participants |
| Weight | 78.45 kg STANDARD_DEVIATION 18.191 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 112 / 112 |
| serious Total, serious adverse events | 76 / 112 |
Outcome results
Primary
Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2)
Best response was assessed by the Independent Response Review Panel(IRRP) after two cycles of treatment. Overall remission(OR) is the sum of complete remission(CR) and complete remission in the absence of platelet recovery(CRp). CR includes normal values for peripheral blood cell counts (absolute neutrophil and platelet) and leukemic blast cells from bone marrow biopsy or aspirate, and absence of extramedullary disease. Partial remission(PR) includes recovery of peripheral blood cells with improved but still abnormal values in leukemic blast cells.
Time frame: approximately Month 2
Population: Full analysis set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clofarabine | Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | Overall Remission (OR=CR+CRp) | 45.5 percentage of participants |
| Clofarabine | Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | Complete Remission (CR) | 37.5 percentage of participants |
| Clofarabine | Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | Complete Remission w/o platelet recovery (CRp) | 8.0 percentage of participants |
| Clofarabine | Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | Partial Remission (PR) | 3.6 percentage of participants |
| Clofarabine | Percentage of Participants Achieving Overall Remission (OR) After No More Than Two Cycles (Approximately Month 2) | Treatment Failure (TF) | 50.9 percentage of participants |
Secondary
Kaplan Meier Estimate for Disease-free Survival (DFS)
DFS was defined as the number of days from achievement of IRRP-determined overall response until IRRP-determined disease recurrence or death (any cause), regardless of intervening alternative antileukemic treatment, plus 1 day.
Time frame: Up to 2 years
Population: Full analysis set (FAS) of participants who achieved remission.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clofarabine | Kaplan Meier Estimate for Disease-free Survival (DFS) | 43.8 weeks |
Secondary
Kaplan Meier Estimate for Duration of Remission (DOR)
DOR was defined as the number of days from achievement of OR as assessed by the Independent Response Review Panel (IRRP) until IRRP-determined disease recurrence or death (any cause), plus 1 day. Participants who initiated alternative antileukemic treatment while in remission were censored on the date the therapy was initiated or on the date of last follow-up.
Time frame: Up to 2 years
Population: Full analysis set (FAS) of participants who achieved remission.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clofarabine | Kaplan Meier Estimate for Duration of Remission (DOR) | 55.6 weeks |
Secondary
Kaplan Meier Estimates for Overall Survival (OS)
OS was defined as the number of days from first dose of clofarabine until death for all participants, plus 1 day.
Time frame: Up to 2 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clofarabine | Kaplan Meier Estimates for Overall Survival (OS) | 40.7 weeks |
Secondary
Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods
Participants with AEs that occurred during the treatment and follow-up periods. AEs were classified according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. Treatment emergent is defined as any event that either first presents after baseline or worsens in severity after baseline. NCI Common Terminology Criteria for Severity: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5= Death related to AE
Time frame: Up to 2 years
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Treatment-emergent AEs (TEAE) | 112 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Treatment-emergent AEs related to study drug | 108 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Treatment-emergent serious AEs | 76 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Treatment-emergent serious AEs related to drug | 41 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Discontinued due to AEs | 7 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Died w/i treatment period-w/i 45 days of last dose | 22 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Died due to drug-related AEs | 4 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Died within 30 days of first dose | 11 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Died w/i 30 days of first dose due to related AEs | 3 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Grade 1: maximum severity rating for any TEAE | 2 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Grade 2: maximum severity rating for any TEAE | 6 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Grade 3: maximum severity rating for any TEAE | 46 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Grade 4: maximum severity rating for any TEAE | 34 participants |
| Clofarabine | Overall Participant Counts Summarizing Adverse Events (AEs) During the Treatment and Follow-up Periods | Grade 5: maximum severity rating for any TEAE | 24 participants |
Secondary
Percentage of Participants Who Died Within Thirty Days of Treatment (30-day Mortality Rate)
Percentage of participants who died within 30 days of the first dose of study drug, regardless of cause.
Time frame: up to Day 30
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine | Percentage of Participants Who Died Within Thirty Days of Treatment (30-day Mortality Rate) | 9.8 percentage of participants |
Other Pre-specified
Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors
The number of participants within each subgroup of baseline prognostic factors of the full analysis set who achieved a best response of either a complete response (CR) or a complete response in the absence of platelet recovery (CRp) as determined by the Independent Response Review Panel following a maximum of two cycles of treatment.
Time frame: approximately Month 2
Population: Full analysis set (FAS) of participants who achieved remission and had baseline prognostic factor
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Age >=70 (n=69) | 27 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Age <70 (n=43) | 24 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Antecedent hematologic disorder - Yes (n=41) | 21 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Antecedent hematologic disorder - No (n=67) | 29 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Antecedent hematologic disorder-Not reported (n=4) | 1 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | ECOG Performance Status = 0-1 (n=87) | 43 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | ECOG Performance Status = 2 (n=25) | 8 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Karyotype = Intermediate (n=46) | 25 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Karyotype = Unfavorable (n=62) | 26 participants |
| Clofarabine | Number of Participants Achieving Overall Remission After A Maximum of Two Cycles by Subgroup of Baseline Prognostic Factors | Karyotype = Not Reported (n=4) | 0 participants |