Acute Myeloid Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Untreated Adult Acute Myeloid Leukemia
Conditions
Brief summary
This phase II trial studies the side effects and best dose of bortezomib when given together with daunorubicin and cytarabine and to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. To define the remission induction response rate (complete response \[CR\] and CR with incomplete platelet recovery \[CRp\]) in older patients with previously untreated acute myeloid leukemia treated with induction therapy comprising bortezomib in combination with daunorubicin hydrochloride and cytarabine. II. To define the maximum tolerated dose of bortezomib when administered in combination with intermediate-dose cytarabine after induction therapy. SECONDARY OBJECTIVES: I. To describe the disease-free survival of patients treated with this regimen. II. To describe the overall survival of patients treated with this regimen. III. To evaluate the treatment-related toxicities in these patients. OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Doses of bortezomib are escalated during remission consolidation therapy. REMISSION INDUCTION THERAPY: Remission induction course 1: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; daunorubicin hydrochloride IV on days 1-3; and cytarabine IV continuously over 168 hours on days 1-7. After completion of remission induction course 1, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a complete response (CR) or partial response (PR) proceed to remission consolidation therapy. Patients achieving a CR with incomplete platelet recovery (CRp) proceed to remission consolidation therapy after platelet counts recover. Patients with persistent leukemia (\>= 20% bone marrow cellularity and \>= 5% bone marrow myeloblasts) proceed to remission induction course 2. REMISSION INDUCTION COURSE 2: Patients receive bortezomib IV over 3-5 seconds on days 1 and 4; daunorubicin hydrochloride IV on days 1 and 2; and cytarabine IV continuously over 120 hours on days 1-5. After completion of remission induction course 2, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or PR proceed to remission consolidation therapy. Patients achieving a CRp proceed to remission consolidation therapy after platelet counts recover. Patients with residual leukemia who do not meet the criteria for PR are removed from the study. REMISSION CONSOLIDATION THERAPY: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and intermediate-dose cytarabine IV over 3 hours on days 1-5. Patients then undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or who demonstrate continuing CR receive a second course of remission consolidation therapy beginning 2-4 weeks after blood counts recover. After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 2 years, and then annually for up to 10 years.
Interventions
DRUGdaunorubicin hydrochloride
Given IV
DRUGcytarabine
Given IV
DRUGbortezomib
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Unequivocally histologically confirmed acute myeloid leukemia (AML) * At least 20% blasts in the bone marrow based on WHO criteria * No acute promyelocytic leukemia (M3) * Antecedent hematologic disorder or myelodysplastic syndromes allowed provided the patient did not receive cytotoxic chemotherapy, including azacitidine and decitabine, for their pre-leukemic disorder * Concurrent enrollment on CALGB-8461 required * Not pregnant or nursing * Fertile patients must use effective contraception * No ataxia, cranial neuropathy, or peripheral neuropathy \>= grade 2 * LVEF \>= 40% by ECHO or MUGA scan * No signs or symptoms of congestive heart failure * DLCO \>= 50% (corrected for hemoglobin) * No prior therapy for leukemia or pre-leukemic disorders, except for the following: * emergency leukapheresis; * emergency treatment for hyperleukocytosis with hydroxyurea; * cranial radiotherapy for CNS leukostasis (one dose only); * growth factor/cytokine support * No other concurrent chemotherapy, except for the following: * I) steroids administered for adrenal failure, hypersensitivity reactions, or septic shock; * II) hormones administered for non-disease-related conditions (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications) * No concurrent palliative radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Remission Induction Response | 2 months | Response was calculated according to Revised International Working Group (IWG) criteria for Acute myeloid leukemia (AML) A response was defined as the portion of participants who achieved a complete response (CR) or CR with incomplete platelet recovery(CRp) during induction. A CR is defined as those with \> 20% cellularity of bone marrow biopsy, no presence of extramedullary leukemia for AML, \<5 % myeloblast cells for bone marrow with peripheral blood and normal complete blood count (absolute neutrophils \> 1000 mL and platelets \>= 100,000 mL). A CRp is defined as a CR except platelets \< 100,000 mL without need for transfusion. |
| Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine | during consolidation cycle 1 (42 days) | DLTs were considered only during the first cycle of consolidation therapy and included grade 3 or 4 sensory or autonomic neuropathy, persistent grade 4 thrombocytopenia or neutropenia at day 42 in the absence of AML,any grade 4 or 5 nonhematologic toxicity, and any grade 3 nonhematologic toxicity (excluding neuropathy and toxicities secondary to neutropenia and sepsis) that did not resolve to grade 2 by day 42 unless attributable to persistent or recurrent AML. Grade 4 anorexia (requiring total parenteral nutrition) and grade 4 fatigue (requiring bed rest) were not considered DLTs. Toxicity was graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grading scale is as follows: grade 1: mild; grade 2: moderate; grade 3: Severe; grade 4: Life Threatening; grade 5: Death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | Duration of study (up to 10 years) | Disease-free survival (DFS) was measured as the interval from achievement of CR until relapse or death, regardless of cause. DFS was estimated using the Kaplan Meier method. |
| Overall Survival | Duration of study (up to 10 years) | Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method. |
Countries
United States
Participant flow
Recruitment details
Between September 2008 and February 2010, 98 participants were recruited at 15 CALGB member institutions and their affiliated hospitals.
Pre-assignment details
Three (3) participants did not begin treatment and were excluded from all analyses per study design
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib + Daunorubicin + Cytarabine Bortezomib:
Induction: 1.3 mg/sq m IV infusion Days 1,4,8,11 (Days 1, 4 only if 2nd induction)
Consolidation: 0.7 OR 1 OR 1.3 mg/sq m IV infusion Days 1,4,8,11
Cytarabine:
Induction: 100 mg/sq m/day CIVI Days 1-7 (Days 1-5 only if 2nd induction) Consolidation: 2 g/sq m/day IV infusion Days 1-5
Daunorubicin Induction: 60 mg/sq m IV infusion Days 1-3 (Days 1-2 if 2nd induction) | 95 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Consolidation | Adverse Event | 1 |
| Consolidation | Death | 1 |
| Consolidation | Non protocol therapy | 13 |
| Consolidation | Progression | 5 |
| Consolidation | Refused | 1 |
| Remission Induction | Adverse Event | 3 |
| Remission Induction | Death | 10 |
| Remission Induction | Failed induction | 8 |
| Remission Induction | Non protocol treatment | 17 |
| Remission Induction | Other, not specified | 5 |
| Remission Induction | Progression | 6 |
| Remission Induction | Refusal | 5 |
Baseline characteristics
| Characteristic | Bortezomib + Daunorubicin + Cytarabine |
|---|---|
| Age, Continuous | 67 years |
| ECOG Performance Status 0 - Fully Active | 31 participants |
| ECOG Performance Status 1 - Ambulatory, restricted strenuous activity | 55 participants |
| ECOG Performance Status 2 - Ambulatory, unable to perform work activities | 9 participants |
| Region of Enrollment United States | 95 participants |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 77 / 95 |
| serious Total, serious adverse events | 43 / 95 |
Outcome results
Primary
Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine
DLTs were considered only during the first cycle of consolidation therapy and included grade 3 or 4 sensory or autonomic neuropathy, persistent grade 4 thrombocytopenia or neutropenia at day 42 in the absence of AML,any grade 4 or 5 nonhematologic toxicity, and any grade 3 nonhematologic toxicity (excluding neuropathy and toxicities secondary to neutropenia and sepsis) that did not resolve to grade 2 by day 42 unless attributable to persistent or recurrent AML. Grade 4 anorexia (requiring total parenteral nutrition) and grade 4 fatigue (requiring bed rest) were not considered DLTs. Toxicity was graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grading scale is as follows: grade 1: mild; grade 2: moderate; grade 3: Severe; grade 4: Life Threatening; grade 5: Death.
Time frame: during consolidation cycle 1 (42 days)
Population: Participants who were registered to bortezomib consolidation were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Daunorubicin + Cytarabine | Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine | 0 participants |
| Bortezomib (1.0 mg/m^2) + Int-DAC | Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine | 0 participants |
| Bortezomib (1.3 mg/m^2) + Int-DAC | Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine | 1 participants |
Primary
Remission Induction Response
Response was calculated according to Revised International Working Group (IWG) criteria for Acute myeloid leukemia (AML) A response was defined as the portion of participants who achieved a complete response (CR) or CR with incomplete platelet recovery(CRp) during induction. A CR is defined as those with \> 20% cellularity of bone marrow biopsy, no presence of extramedullary leukemia for AML, \<5 % myeloblast cells for bone marrow with peripheral blood and normal complete blood count (absolute neutrophils \> 1000 mL and platelets \>= 100,000 mL). A CRp is defined as a CR except platelets \< 100,000 mL without need for transfusion.
Time frame: 2 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bortezomib + Daunorubicin + Cytarabine | Remission Induction Response | Complete response | 62 participants |
| Bortezomib + Daunorubicin + Cytarabine | Remission Induction Response | Complete response with incomplete platelet recover | 4 participants |
Secondary
Disease-free Survival
Disease-free survival (DFS) was measured as the interval from achievement of CR until relapse or death, regardless of cause. DFS was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 10 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib + Daunorubicin + Cytarabine | Disease-free Survival | 8 months |
Secondary
Overall Survival
Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 10 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib + Daunorubicin + Cytarabine | Overall Survival | 12 months |