Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of bendamustine hydrochloride when given together with idarubicin in treating older patients with previously untreated acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Drugs used in chemotherapy, such as bendamustine hydrochloride or idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells

Detailed Description
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PRIMARY OBJECTIVES: I. The maximum tolerated dose (MTD) that is associated with a complete remission (CR) rate of at least 40%, and a rate of grade 3-4 extramedullary toxicity < 30% in patients aged 50 or older with previously untreated AML or high-risk MDS. SECONDARY OBJECTIVES: I. The disease-free survival (DFS), and overall survival (OS) after therapy at each level of the dosing strategy. OUTLINE: This is a phase I, dose-escalation study of bendamustine hydrochloride followed by a phase II study. Patients receive bendamustine hydrochloride intravenously (IV) on days 1-5 and idarubicin IV on days 1 and 2. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then annually thereafter for 3 years.

Official Title
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Safety and Clinical Activity of Treanda® (Bendamustine HCL) and Idarubicin in Combination Therapy for Patients Age >= 50 With Previously Untreated Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Myelodysplastic Syndrome With Isolated Del(5q), Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: bendamustine hydrochloride
* Drug: idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of untreated AML or MDS with 10-19% marrow blasts; patients may be enrolled if they received prior treatment with demethylating agents specifically for the purpose of treating MDS or if they have received a single dose of cytarabine for the control of symptoms related to AML Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Serum creatinine =< 2.0 mg/dL; if serum creatinine > 2.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation Serum bilirubin =< 1.5 x upper limit of normal (ULN) Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 x ULN Alkaline phosphatase =< 2.5 x ULN Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent Males should be willing to use an effective contraceptive method during the study and for a minimum of 6 months after study treatment Women must be postmenopausal or must be willing to use an acceptable method of contraception to avoid pregnancy for the entire period of the study and for at least 3 months after the study; a postmenopausal woman is defined as a woman who has experienced amenorrhea > 12 consecutive months or a woman on hormone replacement therapy with documented follicle-stimulating hormone (FSH) level > 35 mIU/mL; for patients in whom menopausal state is in question, a negative pregnancy test will be required prior to enrollment Exclusion Criteria: Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea or single-dose cytarabine; subjects who are enrolled with high risk MDS (specifically) may have prior treatment with drugs in the class called demethylating agents; examples of these drugs include 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine), and may include approved or experimental drugs not currently used, which fall into this class and may be developed in the future; the patient must have recovered from all acute toxicities from any previous therapy Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) Pregnant or lactating patients Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results Known hypersensitivity to bendamustine (bendamustine hydrochloride) or idarubicin Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF) Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy Other circumstances in which patients with prior malignancies are not excluded, include the following: Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, if definitive treatment for the condition has been completed Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values if hormonal therapy has been initiated, or a radical prostatectomy or definitive radiotherapy has been performed Concurrent hormonal therapy is allowed

Ages Eligible for Study
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Minimum Age: 50 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>Patients receive bendamustine hydrochloride IV on days 1-5 and idarubicin IV on days 1 and 2. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. | Drug: bendamustine hydrochloride<br>* Given IV<br>* Other names: Treanda;Drug: idarubicin<br>* Given IV<br>* Other names: IDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Assessed by cytogenetics/fluorescence in situ hybridization (FISH) and flow cytometry of blood and bone marrow samples. The response criteria defined by Cheson et al. will be used in this study. These criteria are: morphologic leukemia-free state; morphologic complete remission (CR); cytogenetic CR (CRc); molecular CR (CRm); morphologic CR with incomplete blood count recovery (CRi); partial remission (PR); treatment failure; recurrence (progressive disease). | 6 months | 
| Incidence of Greater Than or Equal to Grade 3 Toxicity | Toxicities will be graded using the National Cancer Institute (NCI) Common Toxicity Criteria version 3.0. | Up to day +100 after end of therapy or until the patient received an alternative treatment for leukemia, whatever happens earlier | 
| Maximum Tolerated Dose | A bayesian approach to estimate the MTD of bendamustine associated with a CR rate of at least 40% and with <30% grade 3-4 non-haematological toxicity was used (Wathen et al, 2008).The MTD of bendamustine in combination with idarubicin was determined after two cases of grade 3 toxicity were noted in the three patients entered at the 75 mg/m2 dose. The DLTs were congestive heart failure and mucositis in one patient each. Patients subsequent to this were treated at the 60 mg/m2 bendamustine dose. | 6 months | 
| Median Survival | In a five year following, the median survival was obtained. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS) | In a five year following, the disease free survival was obtained. | 5 years |