Bortezomib, Daunorubicin, and Cytarabine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Dose Escalation and Phase II Study of Bortezomib (IND #58443) Added to Standard Daunorubicin and Cytarabine Therapy for Patients With Previously Untreated Acute Myeloid Leukemia Age 60-75 Years

Conditions
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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

Intervention / Treatment
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* Drug: daunorubicin hydrochloride
* Drug: cytarabine
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (daunorubicin hydrochloride and bortezomib)<br>See Detailed Description | Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: RP-13057;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 months | 
| 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. | during consolidation cycle 1 (42 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Duration of study (up to 10 years) | 
| Overall Survival | Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method. | Duration of study (up to 10 years) |