Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

Condition(s) targeted: Leukemia

Intervention: clofarabine (Drug); cytarabine (Drug); methotrexate (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Bassem I. Razzouk, MD, Study Chair, Affiliation: St. Vincent Indianapolis Hospital
Todd Cooper, DO, Affiliation: Lurleen Wallace Comprehensive Cancer at University of Alabama-Birmingham

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 by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating young patients with refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia.

Official title: A Phase I/II Study of CLOLAR® (Clofarabine, IND# 73, 789) in Combination With Cytarabine in Pediatric Patients With Refractory/Relapsed Leukemia

Study design: Treatment

Primary outcome:

Maximum tolerated dose of clofarabine in combination with cytarabine

Overall response rate

Secondary outcome: Safety and tolerability as measured by CTCAE v3.0

Detailed description: OBJECTIVES:

Primary

- Define the overall response rate (complete remission or remission without platelet

recovery) in pediatric patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with cytarabine.

Secondary

- Determine the safety profile and tolerability of clofarabine when given in combination

with cytarabine in patients with and without prior stem cell transplantation.

OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by a phase II study. Patients are stratified according to disease (acute lymphoblastic leukemia [ALL] vs acute myeloid leukemia [AML]).

- Intrathecal CNS prophylaxis (all patients with ALL and at physicians discretion for

patients with AML): Patients receive intrathecal (IT) cytarabine on day 0 of the first course of induction therapy and IT methotrexate on day 1 of the second course of induction therapy.

- Induction therapy:

- Course 1: Patients receive cytarabine IV over 2 hours on days 1-5 and clofarabine

IV over 2 hours on days 2-6. Patients with ≥ 5% blasts (i. e., M2 or M3 bone marrow) at days 14-21 proceed immediately to course 2 of induction therapy. Patients with < 5% blasts (i. e., M1 bone marrow) may proceed to course 2 of induction therapy at blood count recovery or at day 42.

- Course 2: Patients receive clofarabine IV over 2 hours (at the same dose as in

course 1) followed by cytarabine IV over 2 hours on days 1-5.

During the first course of induction therapy, cohorts of 10 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 10 patients experience dose-limiting toxicity.

After the second course of induction therapy, patients with M2 or M3 bone marrow are removed from the study. Patients with M1 bone marrow proceed to maintenance therapy 14-42 days after day 1 of course 2 of induction therapy.

- Maintenance therapy: Patients receive IT methotrexate on day 0. Patients also receive

clofarabine at the MTD and cytarabine as in course 2 of induction therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.

Minimum age: 1 Year. Maximum age: 30 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed acute myeloid leukemia (AML) or acute lymphoblastic leukemia

(ALL)

- More than 25% blasts in the bone marrow (M3 bone marrow) (ALL)

- At least 5% bone marrow blasts in the bone marrow (M2/M3 bone marrow) with or

without extramedullary disease (AML)

- Disease must have relapsed after or be refractory to prior induction therapy

- AML patients must be in first relapse OR refractory to induction therapy with ≤ 1

attempt at remission induction

- Must have received prior mitoxantrone hydrochloride and cytarabine for newly

diagnosed AML (phase I)

- ALL patients must be in second or third relapse (no more than 3 prior induction

regimens) OR refractory to reinduction in first relapse

- ALL refractory to first induction therapy is not eligible

- No CNS 3 involvement (i. e., WBC ≥ 5/μL in the cerebrospinal fluid with blasts present

on cytospin)

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤

16 years of age) OR ECOG PS 0-2

- Life expectancy ≥ 8 weeks

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min

- Bilirubin ≤ 1. 5 times upper limit of normal (ULN) (conjugated serum bilirubin < ULN if

total bilirubin is elevated)

- ALT < 2. 5 times ULN (unless it is related to leukemic involvement)

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 45% by gated

radionuclide study

- No evidence of dyspnea at rest or exercise intolerance

- Pulse oximetry > 94% at room air

- Amylase ≤ 1. 5 times ULN

- Lipase < 1. 5 times ULN

- No active, uncontrolled grade 3 or 4 infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known hepatitis B or C infection or history of cirrhosis

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy*

- At least 14 days since prior cytotoxic therapy (48 hours since prior hydroxyurea to

decrease WBC)*

- At least 7 days since prior biologic agent*

- At least 14 days since prior monoclonal antibody therapy*

- No more than 1 prior autologous or allogeneic hematopoietic stem cell transplantation

- No evidence of active graft-vs-host disease

- At least 4 months since transplantation

- No other concurrent chemotherapy or immunomodulating agents

- No other concurrent investigational therapy NOTE: *Relapse during maintenance therapy

does not require a waiting period (ALL)

Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham, Birmingham, Alabama 35294, United States; Recruiting
Clinical Trials Office - Lurleen Wallace Comprehensive Cancer, Phone: 205-934-0309

Children's Hospital of Orange County, Orange, California 92868, United States; Recruiting
Violet Shen, Phone: 714-532-8636

Children's National Medical Center, Washington, District of Columbia 20010-2970, United States; Recruiting
Clinical Trials Office - Children's National Medical Center, Phone: 202-884-2549

Children's Memorial Hospital - Chicago, Chicago, Illinois 60614, United States; Recruiting
David O. Walterhouse, Phone: 773-755-6514

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202-5289, United States; Recruiting
Clinical Trials Office - Indiana University Cancer Center, Phone: 317-274-2552

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

C.S. Mott Children's Hospital at University of Michigan Medical Center, Ann Arbor, Michigan 48109-0286, United States; Recruiting
Clinical Trials Office - C.S. Mott Children's Hospital, Phone: 800-865-1125

Masonic Cancer Center at University of Minnesota, Minneapolis, Minnesota 55455, United States; Recruiting
Clinical Trials Office - Masonic Cancer Center at University o, Phone: 612-624-2620

University of Mississippi Cancer Clinic, Jackson, Mississippi 39216-4505, United States; Recruiting
Gail C. Megason, Phone: 601-984-5220

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis, St. Louis, Missouri 63110, United States; Recruiting
Robert J. Hayashi, Phone: 314-454-4118

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Clinical Trials Office - Herbert Irving Comprehensive Cancer C, Phone: 212-305-8615

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States; Recruiting
Clinical Trials Office - Cincinnati Children's Hospital Medica, Phone: 513-636-0161

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Recruiting
Ronald M. Grant, Phone: 416-813-8885

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-9786, United States; Recruiting
Peter Adamson, Phone: 215-590-6359

Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada; Recruiting
Yvan Samson, Phone: 514-345-4969

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States; Recruiting
Clinical Trials Office - St. Jude Children's Research Hospital, Phone: 901-495-4644

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, United States; Recruiting
Clinical Trials Office - Vanderbilt-Ingram Cancer Center, Phone: 800-811-8480

Baylor University Medical Center - Houston, Houston, Texas 77030-2399, United States; Recruiting
Alberto Pappo, Phone: 832-822-4248

Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas, Texas 75390, United States; Recruiting
Clinical Trials Office - Simmons Comprehensive Cancer Center a, Phone: 866-460-4673; 214-648-7097

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2007
Last updated: October 31, 2008