Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01101880
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Locations: 3
• Arm: 1
• Duration (Months): 83
• Patients Per Site: 16.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving clofarabine and cytarabine together with filgrastim works in treating patients with newly diagnosed acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), and/or advanced myeloproliferative neoplasm. Drugs used in chemotherapy, such as clofarabine 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 the drugs in different doses may kill more cancer cells. Colony stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy.

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); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia; Myeloproliferative Neoplasm With 10% Blasts or Higher	Biological: filgrastim; Drug: clofarabine; Drug: cytarabine	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the complete remission (CR) rate of this regimen as compared with 7 + 3 standard induction with the 90 mg/m^2/dose of daunorubicin (historical control) in previously untreated patients with AML or advanced MDS or advanced myeloproliferative neoplasm less than age 65.

SECONDARY OBJECTIVES:

1. To determine the event free survival (EFS), overall survival (OS) and treatment related mortality of this regimen.

2. To assess the toxicity of this regimen in previously untreated patients. III. To determine whether 3 consolidation chemotherapy cycles consisting of G-CSF (filgrastim), clofarabine, and cytarabine (GCLAC) can be administered with prompt recovery of blood counts.

OUTLINE:

INDUCTION THERAPY: Patients receive filgrastim subcutaneously (SC) daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine intravenously (IV) over 1 hour followed by cytarabine IV over 2 hours daily for 5 days.

CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days.

Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue 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 for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study Of Clofarabine With High Dose Cytarabine And G-CSF Priming In Adult Patients Less Than Age 65 With Newly Diagnosed Acute Myeloid Leukemia Or Advanced Myelodysplastic Syndrome and/or Advanced Myeloproliferative Neoplasm
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and colony stimulating factor) INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Biological: filgrastim; Given SC; Other Names: G-CSF Neupogen ; Drug: clofarabine; Given IV; Other Names: CAFdA Clofarex Clolar ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside

Outcome Measures

Primary Outcome Measures

1. Rates of Complete Remission and Complete Remission With Incomplete Recovery of Counts [Up to 5 years]

   With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Complete remission is defined as less than 5% blast cells present in the bone marrow and count recovery (absolute neutrophil count greater than 1000/microL and platelet count greater than 100,000/microL). Complete remission with incomplete recovery of counts is defined as less than 5% blast cells present in the bone marrow without compete count recovery (absolute neutrophil count less than 1000/microL and platelet count less than 100,000/microL).

2. Duration of Remission [Up to 5 years]

   With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Remission is defined as less than 5% blasts in the bone marrow, no appearance of blasts in the peripheral blood, and no extramedullary disease (appearance of leukemic cells in other tissues).

3. Time to Progression [Up to 5 years]

   With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates.

4. Event Free Survival [Up to 5 years]

   Number of patients in remission at a median follow up of 15 months.

5. Treatment-related Mortality (TRM) [Up to 5 years]

   Treatment-related mortality (TRM) data was not collected.

6. Overall Survival [Up to 5 years]

   With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia by World Health Organization (WHO) criteria (except acute promyelocytic leukemia), or myelodysplastic syndrome, RAEB-2 by WHO classification or advanced myeloproliferative neoplasm with >= 10% blasts in the bone marrow or peripheral blood, including chronic myelomonocytic leukemia (CMML)-2 by WHO classification

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2

• 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/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation

• Serum bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome, hemolysis, or hepatic infiltration by the hematologic malignancy

• Aspartate transferase (AST)/alanine transferase (ALT) =< 2.5 x ULN unless elevation is thought to be due to hepatic infiltration by the hematologic malignancy

• 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

• Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment

• Male and female patients must use an effective contraceptive method during the study and for a minimum of 90 days after study treatment

Exclusion Criteria:

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol with the exception of intrathecal chemotherapy administered on days that are not concurrent with clofarabine and cytarabine

• No prior induction chemotherapy for AML; treatment with hydroxyurea is permitted; treatment with imides or hypomethylating agents for preceding hematological disorders is permitted

• 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 significant organ compromise due to systemic fungal, bacterial, viral, or other infection

• Pregnant or lactating patients

• Any significant concurrent illness, condition, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results

• 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 including the following:

• Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study 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 are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed

• Prior allogeneic stem cell transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	Stanford University	Stanford	California	United States	94305
3	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Pamela Becker, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pamela S Becker, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT01101880
• Other Study ID Numbers: 7144; NCI-2010-00282
• First Posted: Apr 12, 2010
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Myeloproliferative Disorders; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Syndrome; Cytarabine; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Period Title: Overall Study
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Overall Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	23 46%
Male	27 54%
Cytogenetic Risk Factor (Count of Participants)
Favorable	4 8%
Intermediate	32 64%
Unfavorable	13 26%
Indeterminate	1 2%
Antecedent hematological disorder (AHD) (Count of Participants)
Count of Participants [Participants]	23 46%
FLT3 ITD mutation status (Count of Participants)
Count of Participants [Participants]	10 20%
WBC (cells x 10^9/L) [Median (Full Range) ]
Median (Full Range) [cells x 10^9/L]	12
Peripheral Blast (percent of white blood cells) [Median (Full Range) ]
Median (Full Range) [percent of white blood cells]	16

Outcome Measures

1. Primary Outcome

Title	Rates of Complete Remission and Complete Remission With Incomplete Recovery of Counts
Description	With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Complete remission is defined as less than 5% blast cells present in the bone marrow and count recovery (absolute neutrophil count greater than 1000/microL and platelet count greater than 100,000/microL). Complete remission with incomplete recovery of counts is defined as less than 5% blast cells present in the bone marrow without compete count recovery (absolute neutrophil count less than 1000/microL and platelet count less than 100,000/microL).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

CR achieved with no AHD only applies to those who did not have AHD.

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	50
CR achieved	38 76%
CR achieved with first course of induction	33 66%
CR + CRp achieved	41 82%
CR achieved with no AHD	23 46%
CR achieved with AHD	15 30%
CR + CRp achieved with AHD	18 36%
CR achieved with FLT3 positive	7 14%
CR achieved with favorable risk cytogenetics	4 8%
CR achieved with intermediate risk cytogenetics	26 52%
CR + CRp achieved with intermediate risk cyto.	27 54%
CR achieved with unfavorable risk cytogenetics	8 16%
CR + CRp achieved with unfavorable risk cyto.	10 20%

2. Primary Outcome

Title	Duration of Remission
Description	With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates. Remission is defined as less than 5% blasts in the bone marrow, no appearance of blasts in the peripheral blood, and no extramedullary disease (appearance of leukemic cells in other tissues).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	9
Median (Full Range) [weeks]	7

3. Primary Outcome

Title	Time to Progression
Description	With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	9
Median (Full Range) [weeks]	7

4. Primary Outcome

Title	Event Free Survival
Description	Number of patients in remission at a median follow up of 15 months.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	50
Count of Participants [Participants]	21 42%

5. Primary Outcome

Title	Treatment-related Mortality (TRM)
Description	Treatment-related mortality (TRM) data was not collected.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Treatment-related mortality (TRM) data was not collected.

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	0

6. Primary Outcome

Title	Overall Survival
Description	With 50 patients, the rates of these endpoints will be estimated with a standard error of 5 to 7 percentage points, depending on the observed rates.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
Measure Participants	50
Median (95% Confidence Interval) [months]	24.3

Adverse Events

Adverse Event Reporting Description	Other [Not including Serious] Adverse Events were not monitored/assessed.
Arm/Group Title	Treatment (Chemotherapy and Colony Stimulating Factor)
Arm/Group Description	INDUCTION THERAPY: Patients receive filgrastim SC daily beginning the day prior to chemotherapy and continuing until blood counts recover. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 5 days. CONSOLIDATION THERAPY: Patients receive filgrastim SC daily for 5 days beginning the day prior to chemotherapy. Patients receive clofarabine IV over 1 hour followed by cytarabine IV over 2 hours daily for 4 days. Treatment with induction therapy may continue for up to 2 courses and treatment with consolidation therapy may continue for up to 3 courses in the absence of disease progression or unacceptable toxicity. filgrastim: Given SC clofarabine: Given IV cytarabine: Given IV
All Cause Mortality
	Treatment (Chemotherapy and Colony Stimulating Factor)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Chemotherapy and Colony Stimulating Factor)
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Blood and lymphatic system disorders
Coagulation	4/50 (8%)	4
Cardiac disorders
Cardiovascular	2/50 (4%)	2
Eye disorders
Ocular	1/50 (2%)	1
Gastrointestinal disorders
Gastrointestinal	10/50 (20%)	10
General disorders
Pain	1/50 (2%)	1
Hepatobiliary disorders
Liver enzymes	20/50 (40%)	20
Hepatobiliary	1/50 (2%)	1
Infections and infestations
infection	50/50 (100%)	95
Metabolism and nutrition disorders
Metabolic	10/50 (20%)	10
Nervous system disorders
Neurologic	6/50 (12%)	6
Renal and urinary disorders
Urinary	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary	31/50 (62%)	31
Skin and subcutaneous tissue disorders
Dermatologic	10/50 (20%)	10
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy and Colony Stimulating Factor)
	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.