Leukemia
Conditions
Keywords
relapsed, refractory, acute, myeloid, AML, CML, blast crisis
Brief summary
The purpose of the study is to find out what effects (good and bad) Gleevec® (Imatinib mesylate) combined with chemotherapy has on participants and their acute myeloid leukemia.
Detailed description
In relapsed or resistant acute myeloid leukemia (a type of blood cancer where immature blood cells are increased, blocking normal blood cell production), different types of chemotherapy are used for treatment. Patients responded to all the chemotherapies in similar ways, but most of the responses did not last long if further stem cell transplantation was not done. Gleevec is believed to work by interfering with the abnormal protein by blocking it from telling the body to keep making more white blood cells that are abnormal. The CLAG regimen is the standard chemotherapy used for relapsed AML (Acute Myeloid Leukemia). This study will add Gleevec® to the regimen for a period of 14 days. Gleevec® is approved by the Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia (CML) and some types of acute lymphoblastic leukemia (ALL). Its use in combination with CLAG regimen is considered experimental for the treatment of Acute Myeloid Leukemia/CML blast crisis.
Interventions
DRUGCLAG Regimen
The CLAG regimen consisted of: Cladribine, 5 mg/m\^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m\^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
DRUGGleevec®
Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR).
Sponsors
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and Women of all ethnic groups whose age is ≥ 18 years old. * Diagnosis of AML or CML blast crisis, according to World Health Organization (WHO) criteria, except acute promyelocytic leukemia AML-M3 French-American-British (FAB) subgroup. A documentation of relapse is required by a bone marrow/aspirate within 4 weeks of registration. * Refractory or Relapsed AML. Refractory AML is defined as failure to achieve CR after 2 cycles of induction chemotherapy or persistent (\>40%) bone marrow blasts after one cycle of chemotherapy induction. * Relapsed AML is defined as any evidence of disease recurrence after achieving complete response (CR) (more than 5% myeloblasts). Early relapse is defined as that occurring within 12 months and late relapse is defines as that occurring after 12 months. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Patients must sign a written informed consent. * Females of childbearing potential (FOCP) must not be pregnant or actively nursing a child. They must have a negative pregnancy test 7 days before initiation of study drug administration * Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. * Male and females of reproductive potential must agree to employ an effective barrier method of birth control throughout the duration of the trial and for 3 months following study medication discontinuation. * Prior allogeneic or autologous stem cell transplantation is allowed.
Exclusion criteria
* Abnormal Kidney Functions: creatinine ≥2.5 mg/dL. * Abnormal Liver Functions: Bilirubin more 3 mg/dL, transaminases (AST/ALT) more than 2.5 times the institutional upper limits of normal (IULN). * Systemic active infection, unless controlled on active therapy. * Patients with Grade III/IV cardiac problems as defined by the New York Heart Association (NYHA) Criteria ( i.e., congestive heart failure, myocardial infarction within 6 months of the study), or ejection fraction (EF)\< 30%. * Patient has known chronic liver disease (i.e., chronic active hepatitis, hepatitis B, hepatitis C, and cirrhosis). * Patient has known diagnosis of human immunodeficiency virus (HIV) infection. * History of other malignancy, except non-melanotic skin cancers or no disease recurrence/progression for more than 2 years. * Patients that have received investigational agents within 1 month of study entry. * History of allergic reaction attributed to compounds of similar chemical or biologic composition to Gleevec or any component of the CLAG regimen * Prior therapy with CLAG chemotherapy regimen * Any adverse event attributable to previous chemotherapy regimen must be resolved to grade 1 or less at time of registration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 8 weeks per participant | Overall Response Rate: Morphologic Complete Remission (CR) + Morphologic Complete Remission with incomplete blood count recovery (CRi) for evaluable participants. CR - Bone Marrow: \< 5% blasts without Auer rods with at least 20% cellularity with maturation of all cell lines, No presence of unique phenotype by flow cytometry identical to what was found in the pretreatment specimen, No persistent dysplasia; Peripheral: normal blood counts, absolute neutrophil count (ANC) \> 1.0 k/μl and platelets \> 100 k/μl ANC \> 1.0 k/μl and platelets \> 100 k/μl (Peripheral blood counts documenting recovery can be utilized within 4 weeks of the bone marrow); No evidence of extramedullary leukemia. CRi - All CR criteria are met except for residual Neutropenia \<1.0 x 10\^9/L platelets \< 100 k/μl. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | Up to 3 years | Progression Free Survival is defined as the duration of time from start of treatment to time of progression. Leukemia related failure (progressive disease): Failure to induce bone marrow hypoplasia after 2 cycles or regrowth of leukemic blasts ≥ 20%. |
| Median Overall Survival (OS) | Up to 3 years | Overall Survival is defined as the time from randomization until death from any cause. |
Countries
United States
Participant flow
Recruitment details
Between August 2009 and April 2011, participants were enrolled at Moffitt Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| CLAG Regimen With Gleevec® Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate).
Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR).
CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m\^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m\^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine. | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | CLAG Regimen With Gleevec® |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 62 years |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 8 / 38 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall Response Rate: Morphologic Complete Remission (CR) + Morphologic Complete Remission with incomplete blood count recovery (CRi) for evaluable participants. CR - Bone Marrow: \< 5% blasts without Auer rods with at least 20% cellularity with maturation of all cell lines, No presence of unique phenotype by flow cytometry identical to what was found in the pretreatment specimen, No persistent dysplasia; Peripheral: normal blood counts, absolute neutrophil count (ANC) \> 1.0 k/μl and platelets \> 100 k/μl ANC \> 1.0 k/μl and platelets \> 100 k/μl (Peripheral blood counts documenting recovery can be utilized within 4 weeks of the bone marrow); No evidence of extramedullary leukemia. CRi - All CR criteria are met except for residual Neutropenia \<1.0 x 10\^9/L platelets \< 100 k/μl.
Time frame: 8 weeks per participant
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CLAG Regimen With Gleevec® | Overall Response Rate (ORR) | 37 percentage of participants |
Secondary
Median Overall Survival (OS)
Overall Survival is defined as the time from randomization until death from any cause.
Time frame: Up to 3 years
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CLAG Regimen With Gleevec® | Median Overall Survival (OS) | 4.9 months |
Secondary
Median Progression Free Survival (PFS)
Progression Free Survival is defined as the duration of time from start of treatment to time of progression. Leukemia related failure (progressive disease): Failure to induce bone marrow hypoplasia after 2 cycles or regrowth of leukemic blasts ≥ 20%.
Time frame: Up to 3 years
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CLAG Regimen With Gleevec® | Median Progression Free Survival (PFS) | 11.1 months |