Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00602225
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Location: 1
• Arm: 1
• Duration (Months): 88
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: 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 stopping them from dividing. Colony stimulating factors, such as G-CSF, 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.

PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine to see how well it works when given together with cytarabine and G-CSF in treating patients with relapsed or refractory acute myeloid leukemia

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia	Drug: clofarabine; Drug: cytarabine; Biological: filgrastim	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the maximum tolerated dose of clofarabine, and the dose-limiting toxicities of the combination of clofarabine and cytarabine with G-CSF priming, in the treatment of patients with relapsed or refractory AML.

SECONDARY OBJECTIVES:

1. To determine the hematological and non-hematological side effect profile of the combination of clofarabine, cytarabine, and G-CSF.

2. To determine the efficacy of clofarabine in combination with cytarabine and G-CSF priming in the treatment of patients with relapsed or refractory AML.

3. To determine the disease-free and overall survival after therapy with clofarabine, cytarabine, and G-CSF for relapsed or refractory AML.

OUTLINE: This is a dose escalation study of clofarabine.

PART I:

INDUCTION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine IV over 2 hours on days 1-5, and filgrastim (G-CSF) subcutaneously once daily beginning 24 hours prior to chemotherapy and continuing until blood count recover. Patients with residual leukemia (>= 5% blasts by morphology) at day 14 and if blast remain > 5% by day 21 receive a second course of induction therapy.

CONSOLIDATION THERAPY: Patients receive clofarabine, cytarabine, and G-CSF as in induction therapy. Patients may receive a second course of consolidation therapy depending on response and whether additional therapy (e.g., stem cell transplant or donor lymphocyte infusion) is planned.

PARTS II and III:

Patients receive induction therapy and consolidation therapy as in part 1.

After completion of study treatment, patients are followed every 3 months for 2 years and then annually for 3 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: Dose Escalation Study of Clofarabine in Combination With Cytarabine (Ara-C) and G-CSF Priming for Relapsed or Refractory Acute Myeloid Leukemia (AML) Patients
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I See Detailed Description	Drug: clofarabine; Given IV; Other Names: CAFdA Clofarex Clolar ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Biological: filgrastim; Given subcutaneously; Other Names: G-CSF Neupogen

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose of Clofarabine [45 days after the last dose of clofarabine]

2. Dose-limiting Toxicity as Assessed by NCI CTCAE v3.0 [45 days after the last dose of clofarabine]

3. Response Rates by Cytogenetic Risk Category [45 days after the last dose of clofarabine]

   Number of participants who achieved Complete Remission (less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) under each cytogenetic risk category.

4. Response Rates by Cytogenetic Risk Category and Clofarabine Dose [45 days after the last dose of clofarabine]

   Number of participants under each Cytogenetic Risk Category and Clofarabine dose who achieve CR (Complete Remission = less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) or CRp (Complete Remission, but with a platelet count of less than 100,000/microL).

5. Response Rates by Duration First Complete Remission (CR1) [45 days after the last dose of clofarabine]

   Number of participants whose first Complete Remission lasted 0, 1-6, 6-12, or greater than 12 months. Only those participant who had a first CR are included in this data.

6. Response Rates by Salvage Number [45 days after the last dose of clofarabine]

   Number of participants in each Salvage number category who achieved a Complete Remission. Salvage number refers to whether treatment with GCLAC on this study was the pariticipant's first salvage regimen (1), second salvage regimen (2), or third or greater salvage regimen (3 or greater).

Secondary Outcome Measures

1. Hematologic and Non-hematologic Side Effect Profile [45 days after the last dose of clofarabine]

2. Efficacy [At five years after the last dose of clofarabine]

   Number of Patients Surviving at Five Years

3. Disease-free Survival [At five years after the last dose of clofarabine]

   Number of participants who survived and were disease-free at 5 years

4. Overall Survival [At five years after the last dose of clofarabine]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• ECOG performance status 0-2

• 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 be willing to use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

• Serum Total or Direct bilirubin =< 1.5 times upper limit of normal (ULN)

• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 times ULN

• Diagnosis of acute myeloid leukemia by WHO criteria, either relapsed or refractory; acute promyelocytic leukemia [acute promyelocytic leukemia with t(15;17)(q22;q12) and variants] would be eligible only after failure of a regimen containing arsenic trioxide

• 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

• Alkaline phosphatase =< 2.5 times ULN

Exclusion Criteria:

• Use of investigational agents within 30 days or initiation of any other anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea, and intrathecal therapy for leukemic meningitis

• 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

• Have any other severe concurrent disease, history of serious organ dysfunction, or disease involving the heart, kidney, liver (including symptomatic hepatitis, veno-occlusive disease, or hepatic graft-versus-host disease [for acute >= grade 2]), or other organ system dysfunction

• No concomitant cytotoxic therapy or investigational therapy is allowed during the study with the exception of intrathecal therapy for leukemic meningitis; intrathecal therapy must not be given during or within 24 hours of any 5 day Clofarabine/Cytarabine treatment period

• To the extent possible, use of nephrotoxic (e.g., vancomycin, amphotericin B, etc) and hepatotoxic (e.g., voriconazole, cyclosporine, etc) agents is to be avoided during clofarabine; use of alternative medications (e.g., herbal or botanical for anticancer purposes) is not permitted during the entire study period

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol

• More than two failed induction attempts for initial diagnosis or current relapse; for patients enrolled under part III of the protocol, patients must be at first salvage after relapse less than one year from complete remission, or salvage after initial induction chemotherapy

• Allogeneic transplant recipients on immunosuppression or on treatment for GVHD

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

• 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: NCT00602225
• Other Study ID Numbers: 6562; NCI-2009-01464
• First Posted: Jan 28, 2008
• Last Update Posted: Mar 9, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Cytarabine; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Period Title: Overall Study
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Overall Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	14 28%
Male	36 72%
AML Onset: de novo (Count of Participants)
Count of Participants [Participants]	32 64%
AML Onset: secondary (Count of Participants)
Count of Participants [Participants]	18 36%
Relapsed (Count of Participants)
Count of Participants [Participants]	32 64%
First salvage (Count of Participants)
Count of Participants [Participants]	32 64%
Second or greater salvage (Count of Participants)
Count of Participants [Participants]	18 36%
Refractory (Count of Participants)
Count of Participants [Participants]	18 36%
Favorable cytogenetics (at initial diagnosis) (Count of Participants)
Count of Participants [Participants]	3 6%
Intermediate cytogenetics (at initial diagnosis) (Count of Participants)
Count of Participants [Participants]	27 54%
Unfavorable cytogenetics (at initial diagnosis) (Count of Participants)
Count of Participants [Participants]	20 40%
Median first CR duration (weeks) [Median (Full Range) ]
Median (Full Range) [weeks]	26

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose of Clofarabine
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	50
Number [mg/m^2 of clofarabine]	25

2. Primary Outcome

Title	Dose-limiting Toxicity as Assessed by NCI CTCAE v3.0
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	50
Count of Participants [Participants]	2 4%

3. Primary Outcome

Title	Response Rates by Cytogenetic Risk Category
Description	Number of participants who achieved Complete Remission (less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) under each cytogenetic risk category.
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	46
Favorable risk Complete Remission	3 6%
Intermediate risk Complete remission	10 20%
Unfavorable risk Complete remission	9 18%

4. Primary Outcome

Title	Response Rates by Cytogenetic Risk Category and Clofarabine Dose
Description	Number of participants under each Cytogenetic Risk Category and Clofarabine dose who achieve CR (Complete Remission = less than 5% blasts in the marrow and count recovery of Absolute Neutrophil Count to 1,000/microL and Platelet Count to 100,000/microL) or CRp (Complete Remission, but with a platelet count of less than 100,000/microL).
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	46
Favorable Risk + 25 mg/m^2 achieve CR	2 4%
Intermediate Risk + 15 mg/m^2 achieve CR	2 4%
Intermediate Risk + 20 mg/m^2 achieve CR	3 6%
Intermediate Risk + 25 mg/m^2 achieve CR	5 10%
Intermediate Risk + 25 mg/m^2 achieve CRp	4 8%
Unfavorable Risk + 15 mg/m^2 achieve CR	2 4%
Unfavorable Risk + 20 mg/m^2 achieve CR	1 2%
Unfavorable Risk + 25 mg/m^2 achieve CR	6 12%
Unfavorable Risk + 25 mg/mg^2 achieve CRp	3 6%

5. Primary Outcome

Title	Response Rates by Duration First Complete Remission (CR1)
Description	Number of participants whose first Complete Remission lasted 0, 1-6, 6-12, or greater than 12 months. Only those participant who had a first CR are included in this data.
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	21
Duration CR1 (months): 0	12 24%
Duration CR1 (months): 1-6	4 8%
Duration CR1 (months): 6-12	2 4%
Duration CR1 (months): greater than 12	3 6%

6. Primary Outcome

Title	Response Rates by Salvage Number
Description	Number of participants in each Salvage number category who achieved a Complete Remission. Salvage number refers to whether treatment with GCLAC on this study was the pariticipant's first salvage regimen (1), second salvage regimen (2), or third or greater salvage regimen (3 or greater).
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

Of the 50 patients, 4 were excluded from analysis of response: 2 patients with GVHD, 1 patient who received only 1 g/m2 ara-C, and 1 patient who did not have a marrow confirming remission status prior to beginning a preparative regimen for allogeneic HCT.

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	46
Salvage number 1	16 32%
Salvage number 2	5 10%
Salvage number 3 or greater	0 0%

7. Secondary Outcome

Title	Hematologic and Non-hematologic Side Effect Profile
Time Frame	45 days after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	0

8. Secondary Outcome

Title	Efficacy
Description	Number of Patients Surviving at Five Years
Time Frame	At five years after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	50
Count of Participants [Participants]	12 24%

9. Secondary Outcome

Title	Disease-free Survival
Description	Number of participants who survived and were disease-free at 5 years
Time Frame	At five years after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Filgrastim + Clofarabine + Cytarabine (GCLAC)
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	50
Count of Participants [Participants]	11 22%

10. Secondary Outcome

Title	Overall Survival
Time Frame	At five years after the last dose of clofarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
Measure Participants	50
Median (95% Confidence Interval) [months]	9

Adverse Events

Adverse Event Reporting Description	Other [Non-serious] adverse events were not collected/assessed.
Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description clofarabine: Given IV cytarabine: Given IV filgrastim: Given subcutaneously
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	23/50 (46%)
Gastrointestinal disorders
Gastrointestinal	6/50 (12%)	6
General disorders
Pain	1/50 (2%)	1
Hepatobiliary disorders
Hepatic transaminases	8/50 (16%)	8
Infections and infestations
infection	20/50 (40%)	20
Investigations
Hyperbilirubinaemia	4/50 (8%)	4
Tumor Lysis	1/50 (2%)	1
Nervous system disorders
Neuropathy	1/50 (2%)	1
Renal and urinary disorders
Renal	2/50 (4%)	2
Respiratory, thoracic and mediastinal disorders
Pulmonary	23/50 (46%)	23
Skin and subcutaneous tissue disorders
Skin	5/50 (10%)	5
Other (Not Including Serious) Adverse Events
	Arm I
	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.