S0530 Cytarabine and Clofarabine in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as cytarabine and clofarabine, 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 II trial is studying how well giving cytarabine together with clofarabine works in treating patients with relapsed or refractory acute lymphoblastic leukemia.

Detailed Description
-----------------
Primary objective: Determine whether the complete remission rate in adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is sufficiently high after treatment with cytarabine and clofarabine to warrant further investigation. Secondary objectives: Estimate the frequency and severity of toxicities associated with this dosing schedule of cytarabine and clofarabine. Investigate, preliminarily, the prognostic effects of cytogenetic features on response to treatment in these patients. Other objectives (if funding allows): Investigate, preliminarily, the prognostic effects of laboratory correlates (expression of nucleoside transporters, expression of other pertinent genes by tissue microarray) and FISH features on response to treatment in these patients OUTLINE: This is an open-label, multicenter study. Induction therapy (1 or 2 courses): Patients receive induction therapy comprising clofarabine IV over 1 hour followed 4 hours later by cytarabine IV over 2 hours on days 1-5 (course 1). Patients who achieve a response (5-25% blasts in the bone marrow with a ≥ 50% reduction in blasts from initial bone marrow aspirate) receive 1 more course of induction therapy beginning no later than day 45. Patients who achieve complete remission (< 5% blasts in the bone marrow) after 1 or 2 courses of induction therapy may proceed to consolidation therapy. Consolidation therapy (1 course): Beginning within 60 days after the first day of the last induction therapy, patients may receive consolidation therapy comprising clofarabine IV over 1 hour followed 4 hours later by cytarabine IV over 2 hours on days 1-4. After completion of study treatment, patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

Official Title
-----------------
A Phase II Trial of Cytarabine and Clofarabine in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Drug: clofarabine
* Drug: cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Prior morphologic diagnosis of acute lymphoblastic leukemia (ALL) No M0, mixed lineage, or L3 (Burkitt's) ALL Refractory to a standard induction regimen OR relapsed after successful prior induction therapy Standard induction regimen is defined as any program of treatment that includes vincristine and prednisone or high-dose cytarabine/mitoxantrone Any number of inductions or remissions allowed Must have evidence of ALL in bone marrow or peripheral blood Immunophenotyping of the blood or bone marrow lymphoblasts must be performed to determine lineage (B cell, T cell, or mixed B/T cell) No extramedullary only disease in the absence of bone marrow or blood involvement Co-expression of myeloid antigens (CD13 and CD33) allowed Patients with Philadelphia chromosome-positive (Ph+) ALL or bcr/abl-positive ALL who were previously eligible for imatinib mesylate treatment must have received imatinib mesylate either alone or in combination with chemotherapy for ALL and must have either failed treatment or been unable to tolerate treatment No CNS involvement as determined by lumbar puncture (for previous CNS history or clinical signs or symptoms of CNS) or by clinical exam (if no previous history or signs/symptoms) Must be registered on SWOG-S9910 and SWOG-9007 PATIENT CHARACTERISTICS: Zubrod performance status 0-2 Creatinine ≤ 1.5 times upper limit of normal (ULN) AST or ALT ≤ 1.5 times ULN Bilirubin ≤ 1.5 times ULN No psychiatric disorders that would interfere with study compliance No uncontrolled systemic fungal, bacterial, viral, or other infection No other severe concurrent disease No other serious or poorly controlled medical condition that would preclude study participation No history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that would preclude study participation HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No pre-existing motor or sensory neuropathy ≥ grade 2 No other prior malignancies, except for the following: Adequately treated basal cell or squamous cell skin cancer In situ cervical cancer Adequately treated stage I or II cancer in complete remission Any other prior cancer for which the patient has been disease free for ≥ 5 years PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy No prior clofarabine More than 2 weeks since prior chemotherapy, major surgery, or other investigational agents More than 6 weeks since prior monoclonal antibodies Prior allogeneic or autologous bone marrow transplant allowed provided the following criteria are met: More than 90 days since transplant No acute graft-versus-host disease (GVHD) ≥ grade 2 OR moderate or severe limited chronic GVHD OR extensive chronic GVHD of any severity Prior maintenance therapy with steroids, vincristine, and/or anti-metabolite agents, such as, but not limited to, mercaptopurine, thioguanine, or methotrexate allowed Concurrent hydroxyurea allowed

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induc, ReInduc, Consol, clofarabine, cytarabine<br>Induction: 40mg/m2/d; IV over 1 hr; days 1-5 Re-induction (if necessary): 40mg/m2/d; IV over 1 hr; days 1-5 Consolidation: 40mg/m2/d; IV over 1 hr; days 1-4 | Drug: clofarabine<br>* Induction: 40mg/m2/d; IV over 1 hr; days 1-5 Re-induction (if necessary): 40mg/m2/d; IV over 1 hr; days 1-5 Consolidation: 40mg/m2/d; IV over 1 hr; days 1-4<br>Drug: cytarabine<br>* Induction: 1g/m2/d; IV over 2 hrs; days 1-5 Re-induction (if necessary): 1g/m2/d; IV over 2 hrs; days 1-5 Consolidation: 1g/m2/d; IV over 2 hrs; days 1-4<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Complete Remission | Complete remission is defined as: less than 5% bone marrow blasts, neutrophils greater or equal to 1,000 per microliter, platelets greater than 100,000 per microliter, no blasts in the peripheral blood, and no extramedullary disease | Between day 28 and day 35 inclusive | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of Nucleoside Transporters | Expression was examined in paraffin-embedded tissue by immunohistochemistry. Intensities were scored on a 0-2+ scale. High expression was a score of 2+. | On average, two weeks before treatment started | 
| Number of Patients With Very Poor Risk Cytogenetics |  | On average, 2 weeks before treatment started | 
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | Patients were assess for adverse events after each induction cycle (up to two cycles) and after the one consolidation cycle | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
recurrent adult acute lymphoblastic leukemia, L1 adult acute lymphoblastic leukemia, L2 adult acute lymphoblastic leukemia, B-cell adult acute lymphoblastic leukemia, T-cell adult acute lymphoblastic leukemia