Clofarabine Plus Low-Dose Cytarabine for Patients With Higher-Risk Myelodysplastic Syndrome (MDS)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01444742
• Collaborator: (none)
• Enrollment: 81
• Location: 1
• Arm: 1
• Actual Duration (Months): 62.5
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if clofarabine when given in combination with cytarabine can help to control myelodysplastic syndrome (MDS) after the disease could not be controlled with standard therapy. The safety of this treatment will also be studied.

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

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

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Myeloproliferative Diseases	Drug: Clofarabine; Drug: Cytarabine	Phase 2

Detailed Description

Induction Cycles:

If you are found to be eligible to take part in the study, on Days 1-5 of each cycle , you will receive clofarabine by vein over 1-2 hours.

On Days 1-7 of each cycle, you will receive cytarabine by injection under the skin over several seconds 2 times a day.

You may receive up to 3 cycles at this dose and schedule (also called "induction cycles"). There are 7 treatment days in each cycle but the total length of one cycle (including rest and recovery period) is usually between 4 and 8 weeks.

Consolidation Cycles:

After you have completed the Induction Cycles, if you show a response to treatment, you can then continue with up to a total of 12 more cycles of therapy, which will be called "consolidation cycles". Not every participant may be able to receive all 12 consolidation cycles. The actual number that you will receive depends on whether or not you maintain the response and how you are able to tolerate ongoing therapy. There will be 4-8 weeks between each consolidation cycle depending on any side effects you may be having and your blood counts.

During consolidation cycles you will receive clofarabine on Days 1-3 by vein over 1-2 hours. You will receive cytarabine by injection under the skin over several seconds 2 times a day .

Induction and Consolidation Cycles:

On the days when you receive clofarabine and cytarabine (Days 1-5 during induction and Days 1-3 during consolidation), the clofarabine will be given about 3-6 hours before the cytarabine injections. You can be taught to give cytarabine injections to yourself. In this case, you can leave the clinic after receiving clofarabine. You will be required to record the injections of cytarabine in a diary unless you receive the treatments while you are in the hospital.

Study Visits:

On Day 1 of every cycle (+/- 7 days):

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

• Your performance status will be recorded.

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

About 4 weeks after you started your first cycle, you may have a bone marrow aspirate to check the status of the disease. After that, you may have repeat bone marrow aspirates when the doctor thinks it is needed.

It is recommended that you stay in Houston for up to the first 4 weeks of treatment. After that, you will need to return to Houston before each induction cycle. If you continue with the consolidation you can receive these treatments by your local oncologist. However, you have to return to Houston at least every 3 months for your study visits.

Length of Study:

You may continue taking the study drugs for up to 15 cycles. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Clofarabine is FDA approved and commercially available for use in pediatric patients with acute lymphoblastic leukemia. Its use in adults and in patients with MDS is investigational.

Cytarabine is FDA approved and commercially available for use in patients with acute myeloid leukemia (AML).

Up to 80 patients will take part in this study. All be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients With Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing After, or Are Refractory to, Hypomethylator Therapy
• Actual Study Start Date: Nov 16, 2011
• Actual Primary Completion Date: Jan 29, 2017
• Actual Study Completion Date: Jan 29, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Clofarabine + Cytarabine Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5)

Drug: Clofarabine; Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3); Other Names: Clofarex Clolar ; Drug: Cytarabine; Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5); Other Names: Ara-C Cytosar DepoCyt Cytosine Arabinosine Hydrochloride

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response (CR) [4 weeks after first cycle]

   Complete Response Criteria (CR must last for at least 4 weeks): Marrow: </= 5% myeloblasts with normal maturation of all cell lines; Persistent dysplasia noted; Blood: Hemoglobin (Hb) >/= 11 g/dL (untransfused, patient not on EPO); Neutrophils >/= 1x109/L (not on myeloid growth factor); Platelets >/= 100 * 109/L (not on thrombopoietic agent); No blasts. Bone marrow aspirate and/or biopsy at the end of course 1 (day 28 +/- 7 days). The method of Thall, Simon, and Estey used to monitor response.

Secondary Outcome Measures

1. Overall Survival (OS) [5 years]

   Overall survival defined as the time interval from study entry date to the date of death due to any cause, measured in days/months. Bayesian time-to-event model used to monitor overall survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age >/= 18 years.

2. Diagnosis of MDS confirmed within 10 weeks prior to study entry according to World Health Organization (WHO) or French-American-British (FAB) criteria. Patients are either not eligible for or choose not to proceed with a stem cell transplant.

3. MDS classified as follows: refractory anemia with excess blasts (RAEB-1) (5%-9% BM blasts); RAEB-2 (10%-19% BM Blasts); chronic myelomonocytic leukemia (CMML) (5%-19% Bone Marrow (BM) blasts); RAEB-t (20%-29% BM blasts) AND/OR by International Prostate Symptom Score (IPSS): intermediate-2 and high risk patients.

4. No response, progression, or relapse (according to 2006 International Working Group (IWG) criteria; see section 8 for details) following at least 4 cycles of either azacitidine or decitabine, or following at least 2 cycles of SGI-110, which were completed within the last 2 years - AND/OR - intolerance to azacitidine, decitabine, or SGI-110 defined as drug-related >/= grade 3 hepatic or renal toxicity leading to treatment discontinuation during the preceding 2 years.

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

6. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.

7. Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

2. Active infection not adequately responding to appropriate antibiotics (i.e. ongoing temperatures of >/= 38 degree Celsius).

3. Total bilirubin >/= 1.5 mg/dL and not related to hemolysis or Gilbert's disease. Patients with total bilirubin >/= 1.5 mg/dL to 3 mg/dL are eligible if at least 75% of the bilirubin is indirect.

4. Alanine transaminase (ALT/SGPT) or aspartate transaminase (AST/SGOT) >/= 2.5 x the upper limit of normal.

5. Serum creatinine > 1.5 mg/dL.

6. Female patients who are pregnant or lactating.

7. Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices (IUD), double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study.

8. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.

9. Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.

10. No prior treatment with cytarabine or clofarabine. Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (eg, G-CSF, Granulocyte-macrophage colony-stimulating factor (GM-CSF), procrit, aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient.

11. Psychiatric illness or social situation that would limit the patient's ability to comply with study requirements.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Guillermo Garcia-Manero, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 15, 2013

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01444742
• Other Study ID Numbers: 2011-0660; NCI-2011-03436
• First Posted: Oct 3, 2011
• Last Update Posted: Jul 3, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Leukemia; Myeloproliferative Diseases; Myelodysplastic Syndrome; (MDS); Relapsing; Refractory; Clofarabine; Clofarex; Clolar; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Cytarabine; Clofarabine

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 11/2011 to 10/2015
Pre-assignment Detail	Of the 81 participants registered, one participant was never treated with the study medication. All Participants were registered at The University of Texas MD Anderson Cancer Center.

Arm/Group Title	Clofarabine + Cytarabine
Arm/Group Description	Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5) Clofarabine: Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3) Cytarabine: Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5)
Period Title: Overall Study
STARTED	81
COMPLETED	80
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Clofarabine + Cytarabine
Arm/Group Description	Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5) Clofarabine: Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3) Cytarabine: Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5)
Overall Participants	81
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 19.8%
>=65 years	65 80.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	71
Sex: Female, Male (Count of Participants)
Female	25 30.9%
Male	56 69.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 4.9%
White	72 88.9%
More than one race	0 0%
Unknown or Not Reported	4 4.9%
Region of Enrollment (Count of Participants)
United States	81 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response (CR)
Description	Complete Response Criteria (CR must last for at least 4 weeks): Marrow: </= 5% myeloblasts with normal maturation of all cell lines; Persistent dysplasia noted; Blood: Hemoglobin (Hb) >/= 11 g/dL (untransfused, patient not on EPO); Neutrophils >/= 1x109/L (not on myeloid growth factor); Platelets >/= 100 * 109/L (not on thrombopoietic agent); No blasts. Bone marrow aspirate and/or biopsy at the end of course 1 (day 28 +/- 7 days). The method of Thall, Simon, and Estey used to monitor response.
Time Frame	4 weeks after first cycle

Outcome Measure Data

Analysis Population Description

One of the eighty-one participants registered on the study were in evaluable for response.

Arm/Group Title	Clofarabine + Cytarabine
Arm/Group Description	Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5) Clofarabine: Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3) Cytarabine: Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5)
Measure Participants	80
Count of Participants [Participants]	19 23.5%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival defined as the time interval from study entry date to the date of death due to any cause, measured in days/months. Bayesian time-to-event model used to monitor overall survival.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clofarabine + Cytarabine
Arm/Group Description	Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5) Clofarabine: Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3) Cytarabine: Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5)
Measure Participants	80
Median (Full Range) [Months]	10.3

Adverse Events

Time Frame	Adverse events captured from the time of participant consent until 30 days after the last dose of drug. AE's can be collected for up to 15 cycles.
Arm/Group Title	Clofarabine + Cytarabine
Arm/Group Description	Induction: Clofarabine 10 mg/m2 1-2 hours by vein daily for 5 days (days 1-5) Cytarabine 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: Clofarabine 10 mg/m2 1-2 hours by vein daily for 3 days (days 1-3) Cytarabine 20 mg subcutaneously twice daily for 5 days (days 1-5) Clofarabine: Induction: 10 mg/m2 by vein over 1-2 hours daily for 5 days (days 1-5) Consolidation: 10 mg/m2 by vein over 1-2 hours daily for 3 days (days 1-3) Cytarabine: Induction: 20 mg subcutaneously twice daily for 7 days (days 1-7) Consolidation: 20 mg subcutaneously twice daily for 5 days (days 1-5)
All Cause Mortality
	Clofarabine + Cytarabine
	Affected / at Risk (%)	# Events
Total	16/81 (19.8%)
Serious Adverse Events
	Clofarabine + Cytarabine
	Affected / at Risk (%)	# Events
Total	57/81 (70.4%)
Blood and lymphatic system disorders
Anemia	1/81 (1.2%)	1
Epistaxis	1/81 (1.2%)	1
Hemorrhage	4/81 (4.9%)	7
Cardiac disorders
Hypotension	1/81 (1.2%)	1
Myocardial Infarction	1/81 (1.2%)	1
Pericardial Tamponade	1/81 (1.2%)	1
Gastrointestinal disorders
Constipation	2/81 (2.5%)	2
Diarrhea	1/81 (1.2%)	1
Nausea and Vomiting	1/81 (1.2%)	1
Rectal Ulcer	1/81 (1.2%)	1
General disorders
Chills	1/81 (1.2%)	1
Death	3/81 (3.7%)	3
Duodenal Ulcer	1/81 (1.2%)	1
Failure to Thrive	1/81 (1.2%)	1
Fall	1/81 (1.2%)	1
Fatigue	1/81 (1.2%)	1
Fever of Unknown Origin	2/81 (2.5%)	3
Infusion Reaction	1/81 (1.2%)	1
Neck Mass	1/81 (1.2%)	1
Pain	1/81 (1.2%)	1
Severe Deconditioning	1/81 (1.2%)	1
Infections and infestations
Bacteremia	2/81 (2.5%)	2
Infection	7/81 (8.6%)	9
Lung Infection	22/81 (27.2%)	26
Neutropenic Fever	25/81 (30.9%)	33
Sepsis	7/81 (8.6%)	7
Metabolism and nutrition disorders
Elevated aspartate aminotransferase (AST)	1/81 (1.2%)	1
Hyperbilirubinemia	1/81 (1.2%)	1
Musculoskeletal and connective tissue disorders
Muscle Weakness	1/81 (1.2%)	1
Pseudogout	1/81 (1.2%)	1
Spinal Fracture	1/81 (1.2%)	1
Nervous system disorders
Memory Impairment	1/81 (1.2%)	2
Syncopal Event	1/81 (1.2%)	1
Renal and urinary disorders
Acute Kidney Injury	1/81 (1.2%)	1
Hepatic Failure	1/81 (1.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/81 (1.2%)	1
Respiratory Distress	1/81 (1.2%)	1
Respiratory Failure	1/81 (1.2%)	1
Skin and subcutaneous tissue disorders
Worsening Sweet Syndrome	1/81 (1.2%)	1
Other (Not Including Serious) Adverse Events
	Clofarabine + Cytarabine
	Affected / at Risk (%)	# Events
Total	46/81 (56.8%)
Gastrointestinal disorders
Constipation	13/81 (16%)	13
Nausea	15/81 (18.5%)	15
General disorders
Fatigue	6/81 (7.4%)	6
Headache	12/81 (14.8%)	12
Infections and infestations
Neutropenic Fever	7/81 (8.6%)	9
Metabolism and nutrition disorders
Elevated Alanine Aminotransferase	17/81 (21%)	17
Hyperbilirubinemia	18/81 (22.2%)	18
Skin and subcutaneous tissue disorders
Rash	19/81 (23.5%)	19

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.