Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Temporarily closed	1 to 30	NCI	COG-AAML0523 AAML0523, NCT00372619

Objectives

Primary

1. To define the overall response rate (complete remission or remission without platelet recovery) in young patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with cytarabine.

Secondary

1. To determine the safety profile and tolerability of clofarabine when given in combination with cytarabine in patients with and without prior stem cell transplantation.
2. To identify apoptosis specific genes that are important in mediating response to clofarabine and cytarabine.
3. To quantitate the level of human equilibrative nucleoside transporter proteins (hENT1 and hENT2) and human concentrative nucleoside transporter proteins (hCNT2 and hCNT3) in blasts of these patients.
4. To determine gene expression profiles at study entry and at time of relapse in order to isolate profiles that may predict response and also to complement apoptosis specific protein arrays.
5. To perform serial measurements of minimal residual disease (MRD) to provide an objective determination of the effectiveness of this treatment regimen and to correlate with post remission events (relapse, death).
6. To perform FLT3/ITD analysis to help determine the prevalence and clinical significance of this somatic mutation in patients with relapsed AML.

Entry Criteria

Disease Characteristics:

• Histologically confirmed diagnosis of 1 of the following:
  • Acute myeloid leukemia (AML) with ≥ 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease
  • Acute lymphoblastic leukemia (ALL) with > 25% blasts in the bone marrow (M3 bone marrow) with or without extramedullary disease
  • Acute leukemia of ambiguous lineage with ≥ 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease
• Disease must have relapsed after or be refractory to prior induction therapy
  • Patients with AML or acute leukemia of ambiguous lineage must be in first relapse OR refractory to first induction therapy with ≤ 1 attempt at remission induction
    • Patients with AML who enroll on the phase I portion of the study must have received prior mitoxantrone hydrochloride and cytarabine for newly diagnosed AML (phase I closed to accrual as of 09/16/09)
  • Patients with ALL must be in second or third relapse (≤ 3 prior induction regimens) OR refractory to reinduction in first relapse
    • Patients with ALL refractory to first induction therapy are not eligible
• No acute promyelocytic leukemia
• No CNS 3 involvement (i.e., WBC ≥ 5/μL in the cerebrospinal fluid with blasts present on cytospin)

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from all prior therapy*
• At least 14 days since prior cytotoxic therapy (except hydroxyurea and intrathecal chemotherapy)*
• 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: *Patients who relapse during ALL maintenance therapy do not require a waiting period.]

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
• Direct bilirubin ≤ 1.5 times upper limit of normal (ULN)
• 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 during and for ≥ 3 months after completion of study treatment
• No known hepatitis B or C infection or history of cirrhosis

Expected Enrollment

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

Outcomes

Maximum tolerated dose of clofarabine in combination with cytarabine (Phase I closed to accrual as of 09/16/09)
Overall response rate

Safety and tolerability as measured by CTCAE v3.0

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]). (Phase I closed to accrual as of 09/16/09)

• Intrathecal CNS prophylaxis (all patients with ALL and at physician's discretion for patients with AML or acute leukemia of ambiguous lineage): Patients receive intrathecal (IT) cytarabine on day 0 of the first course of induction therapy. Patients also receive IT methotrexate on day 1 of the second course of induction therapy and on day 1 of all courses of maintenance therapy.
• Induction therapy:
  • Course 1: Patients receive cytarabine IV over 2 hours and clofarabine IV over 2 hours on days 1-5. 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 followed by cytarabine IV over 2 hours on days 1-5. After the second course of induction therapy, patients with M2 or M3 bone marrow at days 14-21 are removed from the study. Patients with M1 bone marrow proceed to maintenance therapy 14-42 days after the initiation of course 2.

• Maintenance therapy: Patients receive clofarabine and cytarabine as in induction therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo blood and bone marrow sample collection periodically for correlative laboratory studies.

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

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Bassem Razzouk, MD, Protocol chair		Ph: 317-338-4673 Email: bassem.razzouk@stjude.org
Todd Cooper, DO, Protocol co-chair		Ph: 205-939-9285 ext. 5855

Registry Information
Official Title		A Phase I/II Study of CLOLAR® (Clofarabine, IND# 73, 789) in Combination with Cytarabine in Pediatric Patients with Refractory/Relapsed Leukemia
Trial Start Date		2007-03-12
Trial Completion Date		2010-11-19 (estimated)
Registered in ClinicalTrials.gov		NCT00372619
Date Submitted to PDQ		2006-06-30
Information Last Verified		2009-11-24
NCI Grant/Contract Number		CA98543

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