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

Phase 1

Completed

Conditions: Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Acute Myeloid Leukemia
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)

Interventions: Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: bortezomib

Registration Number: NCT00742625

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 95

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment (daunorubicin hydrochloride and bortezomib)	daunorubicin hydrochloride	See Detailed Description
Treatment (daunorubicin hydrochloride and bortezomib)	cytarabine	See Detailed Description
Treatment (daunorubicin hydrochloride and bortezomib)	bortezomib	See Detailed Description

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (22): Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States
Kinston Medical Specialists PA
🇺🇸
Kinston, North Carolina, United States
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Florida Hospital
🇺🇸
Orlando, Florida, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
North Shore-LIJ Health System/Center for Advanced Medicine
🇺🇸
New Hyde Park, New York, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Long Island Jewish Medical Center
🇺🇸
New Hyde Park, New York, United States
Lombardi Comprehensive Cancer Center at Georgetown University
🇺🇸
Washington, District of Columbia, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
University of Missouri - Ellis Fischel
🇺🇸
Columbia, Missouri, United States
North Shore-LIJ Health System CCOP
🇺🇸
Manhasset, New York, United States
Washington Hospital Center
🇺🇸
Washington, District of Columbia, United States
Mount Sinai Medical Center
🇺🇸
New York, New York, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States