Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome

NCT ID: NCT01289457

Last Updated: 2020-02-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 282 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-02
• Study Completion Date: 2017-06-28

Brief Summary

The goal of this clinical research study is to learn if the combination of clofarabine, idarubicin, and cytarabine, or the combination of fludarabine, idarubicin, and cytarabine can help control Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS). The safety of these study drug combinations will also be studied.

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 both strands of DNA (the genetic material of cells). This may cause the cancer cells to die.

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

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 4 groups of 6 participants will be enrolled in the Phase I portion of the study. Up to 280 participants will be enrolled in Phase II.

Phase I:

If you are enrolled in the Phase I portion, the dose of clofarabine you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of clofarabine. Each new group will receive a higher dose of clofarabine than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of clofarabine is found.

All participants will receive the same dose level of idarubicin and cytarabine.

Phase II:

If you are enrolled in the Phase II portion, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups:

• If you are in Group 1, you will receive clofarabine, idarubicin, and cytarabine. You will receive clofarabine at the highest dose that was tolerated in the Phase I portion.
• If you are in Group 2, you will receive fludarabine, idarubicin, and cytarabine.

Study Drug Administration:

Study drug(s) will be given in what are called "cycles." Each cycle is 28 days.

Phase I:

On Days 1-5:

• You will receive clofarabine by vein over about 1 hour.
• You will receive cytarabine by vein over about 2 hours.
• On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

Phase II (Induction):

The first cycle of study drugs is called Induction. If the doctor thinks it is needed, you will have up to 2 Induction cycles.

If you are in Group 1:

On Days 1-5 of each cycle:

• You will receive clofarabine by vein over about 1 hour.
• You will receive cytarabine by vein over about 2 hours.
• On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

If you are in Group 2:

On Days 1-5 of each cycle:

• You will receive fludarabine by vein over about 30 minutes.
• You will receive cytarabine by vein over about 2 hours.
• On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

If the doctor thinks it is needed, you may receive less than 5 days of treatment in the induction cycle.

If the doctor thinks it is needed, your dose level will be reduced after Induction.

Phase II (Consolidation):

If the disease responds to the study drugs, you may receive up to 6 more cycles of study drugs. This is called Consolidation.

If you are in Group 1:

On Days 1-3 of each cycle :

• You will receive clofarabine by vein over about 1 hour.
• You will receive cytarabine by vein over about 2 hours.
• After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive idarubicin by vein over about 30 minutes.

If you are in Group 2:

On Days 1-3 of each cycle:

• You will receive fludarabine by vein over about 30 minutes
• You will receive cytarabine by vein over about 2 hours.
• After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive idarubicin by vein over about 30 minutes

If the cancer does not completely respond after Cycle 1, you may repeat induction (Cycle 1). If the cancer completely responds, you will begin the consolidation cycles.

If the doctor thinks it is needed, you may receive less than 3 days of treatment in the consolidation cycles.

Study Visits:

You will have a physical exam, including measurement of your vital signs before the start of each cycle. Blood (about 2 teaspoons) will be drawn for routine tests every 3-7 days.

On Day 28 of every 2-3 cycles (+/- 7 days), if the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest or up to 8 total cycles. You will no longer be able to take the study drugs if the disease gets worse or intolerable side effects occur.

Your participation on the study will be over once you have completed the long-term follow-up.

Long-Term Follow-up:

Every 3 months for 1 year after you are off study, you will be called and asked how you are feeling, about any side effects you may be having, and about any other drugs you may be taking. These calls should last about 5 minutes each.

This is an investigational study. Cytarabine and Idarubicin are FDA approved and commercially available for the treatment of AML. Fludarabine is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia (CLL). Clofarabine is FDA approved and commercially available for the treatment of acute lymphoblastic leukemia (ALL). The combination of these study drugs is investigational.

Up to 292 patients will take part in Phase I and Phase II of this study. All will be enrolled at MD Anderson.

Conditions

Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Clofarabine + Idarubicin + Cytarabine

Phase I: Clofarabine Starting dose 15 mg/m2 by vein for 5 days (days 1-5) + Idarubicin 10 mg/m2 by vein on day 1-3 + Cytarabine 1 g/m2 by vein on day 1-5.

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

Phase I: 15 mg/m2 by vein (IV) daily for 5 days of a 28 day cycle.

Phase II: Clofarabine (dose selected based on Phase I portion) by vein over approximately 1 hour daily for 5 days (days 1-5) for a 28 day cycle.

Idarubicin

Intervention Type: DRUG

10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.

Cytarabine

Intervention Type: DRUG

1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.

Fludarabine

Intervention Type: DRUG

30 mg/m2 by vein over approximately 30 minutes daily for 5 days (days 1-5).

Group 1 CIA

Phase II, Group 1 CIA (Clofarabine + Idarubicin + Cytarabine): Clofarabine Maximum Tolerated Dose (MTD) based on Phase I by vein on days 1-5; Idarubicin 10 mg/m2 by vein on days 1-3; Cytarabine 1 g/m2 by vein on days 1-5.

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

Phase I: 15 mg/m2 by vein (IV) daily for 5 days of a 28 day cycle.

Phase II: Clofarabine (dose selected based on Phase I portion) by vein over approximately 1 hour daily for 5 days (days 1-5) for a 28 day cycle.

Idarubicin

Intervention Type: DRUG

10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.

Cytarabine

Intervention Type: DRUG

1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.

Group 2 FLAI

Phase II, Group 2 FLAI (Fludarabine + Idarubicin + Cytarabine): Fludarabine 30 mg/m2 by vein on days 1-5; Idarubicin 10 mg/m2 by vein on days 1-3; Cytarabine 1 g/m2 by vein on days 1-5.

Group Type: EXPERIMENTAL

Idarubicin

Intervention Type: DRUG

10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.

Cytarabine

Intervention Type: DRUG

1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.

Fludarabine

Intervention Type: DRUG

30 mg/m2 by vein over approximately 30 minutes daily for 5 days (days 1-5).

Interventions

Clofarabine

Phase I: 15 mg/m2 by vein (IV) daily for 5 days of a 28 day cycle.

Phase II: Clofarabine (dose selected based on Phase I portion) by vein over approximately 1 hour daily for 5 days (days 1-5) for a 28 day cycle.

Intervention Type: DRUG

Idarubicin

10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.

Intervention Type: DRUG

Cytarabine

1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.

Intervention Type: DRUG

Fludarabine

30 mg/m2 by vein over approximately 30 minutes daily for 5 days (days 1-5).

Intervention Type: DRUG

Other Intervention Names

Clofarex; Clolar; Idamycin; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride; Fludara

Eligibility Criteria

Inclusion Criteria

1. Sign an Institutional Review Board (IRB)-approved informed consent document.

2. Age 18 to 60. Patients above the age of 60 only with principal investigator (PI) approval

3. Diagnosis of newly diagnosed AML [other than acute promyelocytic leukemia (APL)] or high-risk (intermediate-2 or high by International Prostate Symptom Score (IPSS) or > 10% blasts, including CMML) MDS. Prior therapy with hydrea and the use of a single or a two day dose of cytarabine (up to 3 g/m2) for emergency use up to 24 hours prior to start of study therapy is allowed. Prior therapy for MDS or other AHD is not allowed.

4. Eastern Cooperative Oncology Group (ECOG) performance status of </= 3 at study entry.

5. Organ function as defined below (unless due to leukemia): Serum creatinine </= 3 mg/dL Total bilirubin </= 2.5 mg/dL , Alanine aminotransferase (ALT) (SGPT) </= 3 * upper limit of normal (ULN) or </= 5 * ULN if related to disease.

6. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days and must agree to practice acceptable contraceptive methods. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential.

7. Cardiac ejection fraction >/= 40% (by either cardiac echo or multiple gated acquisition scan (MUGA) scan). Documentation of recent (</= 6 months from screening) outside reports is acceptable.

Exclusion Criteria

1. Breast feeding females

2. Patients with uncontrolled active infections (viral, bacterial, and fungal are not eligible).

3. Patients with active secondary malignancy will not be eligible.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

M.D. Anderson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elias Jabbour, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Locations

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

Morita K, Kantarjian HM, Wang F, Yan Y, Bueso-Ramos C, Sasaki K, Issa GC, Wang S, Jorgensen J, Song X, Zhang J, Tippen S, Thornton R, Coyle M, Little L, Gumbs C, Pemmaraju N, Daver N, DiNardo CD, Konopleva M, Andreeff M, Ravandi F, Cortes JE, Kadia T, Jabbour E, Garcia-Manero G, Patel KP, Futreal PA, Takahashi K. Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia. J Clin Oncol. 2018 Jun 20;36(18):1788-1797. doi: 10.1200/JCO.2017.77.6757. Epub 2018 Apr 27.

Reference Type: DERIVED

PMID: 29702001 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.mdanderson.org

University of Texas MD Anderson Cancer Center Website

Other Identifiers

NCI-2011-00251

Identifier Type: REGISTRY

Identifier Source: secondary_id

2010-0788

Identifier Type: -

Identifier Source: org_study_id