Clofarabine, Idarubicin, and Cytarabine Combination in Acute Myeloid Leukemia (AML) Induction

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01025154
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 63
• Location: 1
• Arm: 1
• Duration (Months): 37
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if the combination of clofarabine, cytarabine, and idarubicin can help to control Acute Myeloid Leukemia (AML) in patients who are between the ages of 18 and 60 years old. The safety of this study drug combination will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Clofarabine; Drug: Idarubicin; Drug: Cytarabine	Phase 2

Detailed Description

The Study Drugs:

Clofarabine is designed to interfere with the growth and development of cancer cells.

Idarubicin is designed to cause breaks in DNA (the genetic material of cells) of cancer cells and interfere with their growth and development.

Cytarabine is designed to insert itself into DNA of cancer cells and stop the DNA from repairing itself.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive the study drug combination over 1 or 2 "Induction Cycles" of treatment. Whether or not you receive a second Induction Cycle depends on the disease's response to the first Induction Cycle. Each Induction Cycle will last about 4-6 weeks, depending on your reaction to the study drugs.

During each Induction Cycle, you will receive the study drugs by the following schedule:

• Clofarabine, by vein, over 1-2 hours on Days 1-5.

• Cytarabine, by vein, over 2-3 hours on Days 1-5.

• Idarubicin, by vein, over about 30-60 minutes on Days 1-3.

If the disease shows a response to the treatment during the Induction Cycle(s), you may continue to receive up to 6 "Consolidation Cycles" of treatment. Each Consolidation Cycle will last about 3-10 weeks, depending on your reaction to the study drugs. During each

Consolidation Cycle, you will receive the study drugs by the following schedule:

• Clofarabine, by vein, over 1-2 hours on Days 1-3.

• Cytarabine, by vein, over 2-3 hours on Days 1-3.

• Idarubicin, by vein, over 30-60 minutes on Days 1-2.

Study Visits:

On Day 1 of every cycle:

• You will have a physical exam, including measurement of your weight and vital signs.

• Your performance status will be recorded.

• Blood (about 1-2 teaspoons) will be drawn for routine tests.

Throughout the study, you will have blood and bone marrow tests to check the status of the disease and to help the doctor decide if you need additional cycles of treatment. Blood (about 1-2 tablespoons each time) will be drawn 2 times each week for routine tests during the Induction Cycles. This blood will also be drawn every week during the Consolidation Cycles.

About 3 weeks after you first receive the study drugs, you will have a bone marrow aspirate to check the status of the disease. After that, you will have a bone marrow aspirate every 2 weeks (or more often if your doctor thinks it is needed). However, if the routine blood tests show that there is still leukemia present, these bone marrow samples may not need to be collected.

You will need to stay in Houston for up to the first 5 weeks of treatment. After that, you will need to return to Houston to receive treatment, but you can have check-up visits and blood tests with your local doctor in between treatments.

Length of Study:

You will be able to receive the study drugs for up to 8 cycles (a maximum of 2 induction cycles and 6 consolidation cycles). You will be taken off study if the disease gets worse or you experience any intolerable side effects.

Follow-up Scan:

Within 8 weeks after you have stopped taking the study drug, you will have an echocardiogram or a Multiple gate acquisition scan (MUGA) scan to check your heart function.

This is an investigational study. Cytarabine and idarubicin are both FDA approved and commercially available for the treatment of patients with AML. Clofarabine is FDA approved and commercially available for the treatment of patients with acute lymphoblastic leukemia (ALL). The use of this drug combination for the treatment of AML is investigational.

Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clofarabine, Idarubicin, and Cytarabine Combination as Induction Therapy for Younger Patients With Acute Myeloid Leukemia (AML)
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Clofarabine, Cytarabine + Idarubicin Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days

Drug: Clofarabine; Induction Cycle: 20 mg/m^2 IV over approximately 1 hour daily for 5 days (days 1-5); Other Names: Clofarex Clolar ; Drug: Idarubicin; Induction Cycle: 10 mg/m^2 IV over approximately 30 minutes daily for 3 days (days 1-3), following clofarabine by 1 to 2 hours; Other Names: Idamycin ; Drug: Cytarabine; Induction Cycle: 1 g/m^2 IV over approximately 2 hours daily for 5 days (days 1-5), follow clofarabine by 3 to 6 hours.; Other Names: Ara-C Cytosar DepoCyt Cytosine Arabinosine Hydrochloride

Outcome Measures

Primary Outcome Measures

1. Overall Response: Number of Participants With Complete Remission or Complete Remission Without Platelet Recovery [8 weeks after Induction therapy (induction cycle 4-6 weeks)]

   Overall Response (CR+CRp) defined as Complete remission (CR): Disappearance of all clinical and/or radiologic evidence of disease. Neutrophil count > 1.0 x 10^9/L and platelet count > 100 x 10^9/L, and normal bone marrow differential (< 5% blasts); and, Complete Remission without Platelet Recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of < 100 x 10^9/L. Response evaluated within 8 weeks after induction therapy.

2. Median Event-Free Survival (EFS) [2 years]

   Event-free survival (EFS) defined as time from start of treatment to first documentation of disease relapse or death. Bayesian time-to-event model will be used to monitor progression free survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of AML (World Health Organization (WHO) classification)

2. Patients must be chemotherapy-naïve, i.e. not have received any prior cytotoxic chemotherapy for AML (with the exception of hydroxyurea). They could have received prior therapy with hypomethylating agents, targeted, or biological agents.

3. Age 18 to 60 years.

4. Eastern Cooperative Oncology Group (ECOG) performance status </= 2.

5. Serum creatinine </= 1.0 mg/dL; if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73m^{2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73m}2)=186 * (serum creatinine)^{-1.154 x (age in years)}-0.023 * (0.742 if patient is female) * (1.212 if patient is black), where SCr is serum creatinine measured in mg/dL. serum bilirubin </= 1.5 * upper limit of normal (ULN) (unless increase is due to hemolysis or a congenital disorder); serum transaminases (SGPT and/or SGOT) </= 2.5 * ULN.

6. Cardiac ejection fraction >/= 45% (by either echocardiography or MUGA scan).

7. Ability to understand and provide signed informed consent.

Exclusion Criteria:

1. Patients with acute promyelocytic leukemia (APL).

2. Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results.

3. Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, intrauterine device (IUD), diaphragm, abstinence, or condoms by their partner) over the entire course of therapy.

4. Active and uncontrolled infection requiring therapy with IV antibiotics or antifungal therapy. Prior or concurrent history of one or more opportunistic infections (e.g., cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Genzyme, a Sanofi Company

Investigators

• Study Chair: Stefan Faderl, MD, UT MD Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The University of Texas (UT) MD Anderson Cancer Center Official Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01025154
• Other Study ID Numbers: 2009-0431
• First Posted: Dec 3, 2009
• Last Update Posted: Oct 9, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by M.D. Anderson Cancer Center: Leukemia; AML; chemotherapy-naïve; Clofarabine; Clofarex; Clolar; Idarubicin; Idamycin; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Clofarabine; Idarubicin

Study Results

Participant Flow

Recruitment Details	Recruitment Period 1/28/2010 - 2/20/2013; All participants were registered at The University of Texas MD Anderson Cancer Center.
Pre-assignment Detail	Of the 63 participants registered, four (4) were excluded prior to study starting.

Arm/Group Title	Clofarabine, Cytarabine + Idarubicin
Arm/Group Description	Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days
Period Title: Overall Study
STARTED	59
COMPLETED	57
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Clofarabine, Cytarabine + Idarubicin
Arm/Group Description	Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days
Overall Participants	59
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48
Sex: Female, Male (Count of Participants)
Female	32 54.2%
Male	27 45.8%
Region of Enrollment (participants) [Number]
United States	59 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response: Number of Participants With Complete Remission or Complete Remission Without Platelet Recovery
Description	Overall Response (CR+CRp) defined as Complete remission (CR): Disappearance of all clinical and/or radiologic evidence of disease. Neutrophil count > 1.0 x 10^9/L and platelet count > 100 x 10^9/L, and normal bone marrow differential (< 5% blasts); and, Complete Remission without Platelet Recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of < 100 x 10^9/L. Response evaluated within 8 weeks after induction therapy.
Time Frame	8 weeks after Induction therapy (induction cycle 4-6 weeks)

Outcome Measure Data

Analysis Population Description

Two of the fifty-nine participants were not evaluable.

Arm/Group Title	Clofarabine, Cytarabine + Idarubicin
Arm/Group Description	Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days
Measure Participants	57
Complete Remission	42 71.2%
Complete Remission without Platelet Recovery	3 5.1%

2. Primary Outcome

Title	Median Event-Free Survival (EFS)
Description	Event-free survival (EFS) defined as time from start of treatment to first documentation of disease relapse or death. Bayesian time-to-event model will be used to monitor progression free survival.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Two of the fifty-nine participants were not included in the analysis.

Arm/Group Title	Clofarabine, Cytarabine + Idarubicin
Arm/Group Description	Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days
Measure Participants	57
Median (Full Range) [Months]	13.5

Adverse Events

Time Frame	1 Year
Arm/Group Title	Clofarabine, Cytarabine + Idarubicin
Arm/Group Description	Induction Cycle: Clofarabine 20 mg/m^2 intravenous (IV) daily for 5 days; Idarubicin 10 mg/m^2 IV daily for 3 days; Cytarabine 1 g/m^2 IV daily for 5 days
All Cause Mortality
	Clofarabine, Cytarabine + Idarubicin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Clofarabine, Cytarabine + Idarubicin
	Affected / at Risk (%)	# Events
Total	36/59 (61%)
Cardiac disorders
Atrial Fibrillation	1/59 (1.7%)	1
General disorders
Pain	2/59 (3.4%)	3
Headache	1/59 (1.7%)	1
Infections and infestations
Febrile Neutropenia	19/59 (32.2%)	30
Infection	17/59 (28.8%)	24
Nervous system disorders
Seizure	1/59 (1.7%)	1
Somnolence	1/59 (1.7%)	1
Renal and urinary disorders
Renal Failure	1/59 (1.7%)	1
Skin and subcutaneous tissue disorders
Erythema Multiforme	1/59 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Clofarabine, Cytarabine + Idarubicin
	Affected / at Risk (%)	# Events
Total	56/59 (94.9%)
Gastrointestinal disorders
Constipation	5/59 (8.5%)	5
Diarrhea	14/59 (23.7%)	14
Mucositis/stomatitis	6/59 (10.2%)	6
Nausea	24/59 (40.7%)	25
Vomiting	3/59 (5.1%)	3
Pain	14/59 (23.7%)	14
Infections and infestations
Febrile Neutropenia/fever of unknown origin	14/59 (23.7%)	16
Infection	7/59 (11.9%)	7
Metabolism and nutrition disorders
Elevated ALT/AST	11/59 (18.6%)	11
Hyperbilirubinemia	9/59 (15.3%)	9
Hyperkalemia	6/59 (10.2%)	6
Skin and subcutaneous tissue disorders
Rash/desquamation	19/59 (32.2%)	20
Rash/hand-foot skin reaction	4/59 (6.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.