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

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01141725
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 39
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
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	Drug: bendamustine hydrochloride; Drug: idarubicin	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (combination chemotherapy) 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; Given IV; Other Names: bendamustin hydrochloride bendamustine cytostasan hydrochloride Treanda ; Drug: idarubicin; Given IV; Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA

Outcome Measures

Primary Outcome Measures

1. Response [6 months]

   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).

2. Incidence of Greater Than or Equal to Grade 3 Toxicity [Up to day +100 after end of therapy or until the patient received an alternative treatment for leukemia, whatever happens earlier]

   Toxicities will be graded using the National Cancer Institute (NCI) Common Toxicity Criteria version 3.0.

3. Maximum Tolerated Dose [6 months]

   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.

4. Median Survival [5 years]

   In a five year following, the median survival was obtained.

Secondary Outcome Measures

1. Disease-free Survival (DFS) [5 years]

   In a five year following, the disease free survival was obtained.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John Pagel, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT01141725
• Other Study ID Numbers: 2413.00; NCI-2010-01253; K12CA076930
• First Posted: Jun 10, 2010
• Last Update Posted: Aug 18, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Bendamustine Hydrochloride; Idarubicin

Study Results

Participant Flow

Arm/Group Title	Bendamustine Dose of 45mg/m2/Day	Bendamustine Dose of 60mg/m2/Day	Bendamustine Dose of 75mg/m2/Day
Arm/Group Description	Patients receive bendamustine hydrochloride 45mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 60mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 75mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.
Period Title: Overall Study
STARTED	3	33	3
COMPLETED	3	33	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	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. bendamustine hydrochloride: Given IV idarubicin: Given IV
Overall Participants	39
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	73
Sex: Female, Male (Count of Participants)
Female	24 61.5%
Male	15 38.5%
Region of Enrollment (participants) [Number]
United States	39 100%
ECOG (Count of Participants)
ECOG 0	0 0%
ECOG 1	35 89.7%
ECOG 2	4 10.3%

Outcome Measures

1. Primary Outcome

Title	Response
Description	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).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Patients receive bendamustine hydrochloride 45mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 60mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 75mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.
Measure Participants	3	33	3
CR	0 0%	10 NaN	1 NaN
CRi	0 0%	2 NaN	0 NaN
No CR	3 7.7%	21 NaN	2 NaN

2. Primary Outcome

Title	Incidence of Greater Than or Equal to Grade 3 Toxicity
Description	Toxicities will be graded using the National Cancer Institute (NCI) Common Toxicity Criteria version 3.0.
Time Frame	Up to day +100 after end of therapy or until the patient received an alternative treatment for leukemia, whatever happens earlier

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Patients receive bendamustine hydrochloride 45mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 60mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.	Patients receive bendamustine hydrochloride 75mg/m2 IV on days 1-5 and idarubicin 12mg/m2 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.
Measure Participants	3	33	3
Count of Participants [Participants]	0 0%	0 NaN	2 NaN

3. Primary Outcome

Title	Maximum Tolerated Dose
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	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. bendamustine hydrochloride: Given IV idarubicin: Given IV
Measure Participants	39
Number [mg/m2]	60

4. Primary Outcome

Title	Median Survival
Description	In a five year following, the median survival was obtained.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	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. bendamustine hydrochloride: Given IV idarubicin: Given IV
Measure Participants	39
Median (Full Range) [months]	7.2

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for this Outcome Measure was not collected per dose level and is unavailable.

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	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. bendamustine hydrochloride: Given IV idarubicin: Given IV
Measure Participants	39
Median (95% Confidence Interval) [days]	235

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Other (Not Including Serious) Adverse Events were not collected/assessed.
Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	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. bendamustine hydrochloride: Given IV idarubicin: Given IV Adverse event report was not collected by dose level.
All Cause Mortality
	Treatment (Combination Chemotherapy)
	Affected / at Risk (%)	# Events
Total	4/39 (10.3%)
Serious Adverse Events
	Treatment (Combination Chemotherapy)
	Affected / at Risk (%)	# Events
Total	29/39 (74.4%)
Blood and lymphatic system disorders
Febrile Neutropenia	29/39 (74.4%)	29
Platelet transfusion refractory	1/39 (2.6%)	1
Intracranial bleeding	1/39 (2.6%)	1
Cardiac disorders
Heart Failure	1/39 (2.6%)	1
Atrial Fibrillation	1/39 (2.6%)	1
General disorders
Dehydration	1/39 (2.6%)	1
Infections and infestations
Fungal infection	4/39 (10.3%)	4
Bacteraemia	2/39 (5.1%)	2
Sepsis	2/39 (5.1%)	2
Sinusitis	1/39 (2.6%)	1
Severe mucositis	1/39 (2.6%)	1
Clostridium difficile infection	1/39 (2.6%)	1
Renal and urinary disorders
Acute renal injury	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/39 (5.1%)	2
Hypoxia	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Cellulitis	2/39 (5.1%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Combination Chemotherapy)
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.