Bortezomib, Daunorubicin, and Cytarabine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia
This phase II trial is studying 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.
Drug: daunorubicin hydrochloride
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Dose Escalation and Phase II Study of Bortezomib (IND #58443, NSC # 681239) Added to Standard Daunorubicin and Cytarabine Therapy for Patients With Previously Untreated Acute Myeloid Leukemia Age 60-75 Years|
- Remission Induction Response [ Time Frame: 2 months ] [ Designated as safety issue: No ]
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 [ Time Frame: during consolidation cycle 1 (42 days) ] [ Designated as safety issue: Yes ]
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.
- Disease-free Survival [ Time Frame: Duration of study (up to 10 years) ] [ Designated as safety issue: No ]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 [ Time Frame: Duration of study (up to 10 years) ] [ Designated as safety issue: No ]Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.
|Study Start Date:||September 2008|
|Study Completion Date:||December 2012|
|Primary Completion Date:||July 2010 (Final data collection date for primary outcome measure)|
Experimental: Bortezomib + Daunorubicin + Cytarabine
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
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)
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 1,4,8,11Drug: 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 1-5Drug: daunorubicin hydrochloride
Induction: 60 mg/sq m IV infusion Days 1-3 (Days 1-2 if 2nd induction)
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.
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.
Hide Study Locations
|United States, Delaware|
|Tunnell Cancer Center at Beebe Medical Center|
|Lewes, Delaware, United States, 19958|
|CCOP - Christiana Care Health Services|
|Newark, Delaware, United States, 19713|
|United States, District of Columbia|
|Lombardi Comprehensive Cancer Center at Georgetown University Medical Center|
|Washington, District of Columbia, United States, 20007|
|Washington Cancer Institute at Washington Hospital Center|
|Washington, District of Columbia, United States, 20010|
|United States, Florida|
|Florida Hospital Cancer Institute at Florida Hospital Orlando|
|Orlando, Florida, United States, 32803-1273|
|United States, Illinois|
|University of Chicago Cancer Research Center|
|Chicago, Illinois, United States, 60637-1470|
|United States, Indiana|
|Fort Wayne Medical Oncology and Hematology|
|Fort Wayne, Indiana, United States, 46845|
|United States, Iowa|
|Holden Comprehensive Cancer Center at University of Iowa|
|Iowa City, Iowa, United States, 52242-1002|
|United States, Maine|
|CancerCare of Maine at Eastern Maine Medical Center|
|Bangor, Maine, United States, 04401|
|United States, Maryland|
|Greenebaum Cancer Center at University of Maryland Medical Center|
|Baltimore, Maryland, United States, 21201|
|Union Hospital Cancer Program at Union Hospital|
|Elkton MD, Maryland, United States, 21921|
|United States, Massachusetts|
|Dana-Farber/Brigham and Women's Cancer Center|
|Boston, Massachusetts, United States, 02115|
|Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute|
|Boston, Massachusetts, United States, 02115|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|United States, Missouri|
|Ellis Fischel Cancer Center at University of Missouri - Columbia|
|Columbia, Missouri, United States, 65203|
|United States, Nebraska|
|UNMC Eppley Cancer Center at the University of Nebraska Medical Center|
|Omaha, Nebraska, United States, 68198-6805|
|United States, New Jersey|
|Cancer Institute of New Jersey at Cooper - Voorhees|
|Voorhees, New Jersey, United States, 08043|
|United States, New York|
|Roswell Park Cancer Institute|
|Buffalo, New York, United States, 14263-0001|
|Monter Cancer Center of the North Shore-LIJ Health System|
|Lake Success, New York, United States, 11042|
|Don Monti Comprehensive Cancer Center at North Shore University Hospital|
|Manhasset, New York, United States, 11030|
|CCOP - North Shore University Hospital|
|Manhasset, New York, United States, 11030|
|Long Island Jewish Medical Center|
|New Hyde Park, New York, United States, 11040|
|Mount Sinai Medical Center|
|New York, New York, United States, 10029|
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599-7295|
|Wayne Memorial Hospital, Incorporated|
|Goldsboro, North Carolina, United States, 27534|
|Kinston Medical Specialists|
|Kinston, North Carolina, United States, 28501|
|Wake Forest University Comprehensive Cancer Center|
|Winston-Salem, North Carolina, United States, 27157-1096|
|United States, Ohio|
|Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center|
|Columbus, Ohio, United States, 43210-1240|
|United States, Virginia|
|Virginia Commonwealth University Massey Cancer Center|
|Richmond, Virginia, United States, 23298-0037|
|Study Chair:||Eyal C. Attar, MD||Massachusetts General Hospital|