Clinical trial NCT01289457: Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome
Official title: Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Keywords: Acute Myelogenous Leukemia
AML
High-Risk Myelodysplastic Syndrome
MDS
Relapsed
Refractory
Clofarabine
Clofarex
Clolar
Idarubicin
Idamycin
Cytarabine
Ara-C
Cytosar
DepoCyt
Cytosine Arabinosine Hydrochloride
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
First posted: 2011-02-03
Enrollment: 282
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of Clofarabine, Idarubicin, and Cytarabine
timeFrame: 28 days
Secondary outcomes:
measure: Response Rates of Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI)
timeFrame: 12 months
measure: Event-Free Survival (EFS) at 2 Years
timeFrame: Up to 2 years or until relapse/death
measure: Overall Survival
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Elias Jabbour, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.