Clofarabine, Cytarabine and Mitoxantrone (CLAM) for Relapsed or Refractory AML

Study Overview
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Brief Summary
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The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML when used as first salvage for patients to relapse or fail after standard treatment with daunorubicin/cytarabine induction.

Detailed Description
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Clofarabine, a second generation purine nucleoside analog, has been evaluated in several studies in relapsed AML.[1-3] Safety and dosages of clorafabine have already been determined in previous phase I/II studies. A demonstrable complete remission rate of up to 40% to 50% was shown in relapsed or refractory AML.[4-6] Since 2009, Clofarabine (40mg/m2/day for 5 days) in combination with high-dose cytarabine (2g/m2/day for 5 days) (CLARA) was adopted as the re-induction protocol for relapsed or refractory patients with AML at the Department of Medicine, Queen Mary Hospital. We have shown that this protocol is safe, tolerable and effective for relapsed AML. A recent updated analysis (Gill H et al., unpublished) showed a completed response rate of 50.8%. With the CLARA regimen, all patients (N=60) developed grade 3/4 neutropenia and thrombocytopenia. 8% developed grade 3/4 hepatotoxicity and 40% developed febrile neutropenia with clinical sepsis. There is increasing evidence to show that clofarabine is safe and efficacious when combined with the anthracyclines idarubicin or daunorubicin.7,8 In this prospective study, we combine clofarabine and cytarabine (Ara-C) with the topoisomerase II inhibitor mitoxantrone. In this protocol, the dosages of clofarabine and cytarabine will be reduced to 30mg/m2/day and 750mg/m2/day respectively, comparable to most clinical trials. In our previous publication of experience with the use of CLARA by Tse et al and Leung et al, clofarabine at 40mg/m2/day for 5 days was combined with high-dose cytarabine at 2g/m2/day.[5,6] The regimen was shown to be safe. The combination of clofarabine with anthracyclines has been evaluated. Mathiesen at al evaluated the CIA regimen comprising clofarabine at 20mg/m2/day from day 1 to day 5, idarubicin at 10mg/m2/day from day 1 to day 3 and cytarabine at 1g/m2/day from day 1 to day 5.[7] Abbie et al investigated the regimen comprising Clofarabine at 20mg/m2/day or 25mg/m2/day for 5 days in combination with mitoxantrone and etoposide.7 Based on the clinical trials and our extensive experience with the use of CLARA, the dosages of clofarabine in CLAM was determined. With the significant reduction in the dose of cytarabine to 750mg/m2/day for 5 days in CLAM, the dose of clofarabine was chosen at 30mg/m2/day for 5 days with the aim to maintain the efficacy seen with CLARA. The aim of this combination is to maintain or improve treatment efficacy seen with a lower treatment-related toxicity via dose reduction of clofarabine and cytarabine compared to CLARA. CLAM is expected to be safe and tolerable especially when used as first salvage in patient with a ECOG performance status of 0 or 1. The regimen CLAM has been approved by the institutional review board of Queen Mary Hospital/University of Hong Kong. In a pilot study, 4 patients used the regimen. 2 patients achieved a complete remission. Cardiotoxicity was not seen. Grade 3/4 hepatotoxicity was not seen. There were no treatment-related mortality observed. CLAM was shown to be safe and with manageable toxicity profile. In addition, less myeloid toxicity is expected during consolidation as patients who achieve a remission will have better marrow reserve when compared to those at relapse. Patients will have their cardiac, liver and renal function and performance status evaluated continuously and patients with cardiac dysfunction, significantly impaired renal or liver function and ECOG performance status of 2 or above will be excluded. Thus consolidation with the same dose as with induction is expected to be safe and tolerable. The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML when used as first salvage for patients to relapse or fail after standard treatment with daunorubicin/cytarabine induction. We aim to improve treatment efficacy at a more tolerable dose of clofarabine and cytarabine compared to CLARA.

Official Title
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Clofarabine, Cytarabine and Mitoxantrone (CLAM) for Relapsed or Refractory AML

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Clofarabine, AraC, mitoxantrone (CLAM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory acute myeloid leukemia (AML) after one first-line chemotherapy regimen Patients aged 18 - 65 inclusively European Cooperative Oncology Group (ECOG) performance status of less than 2 Exclusion Criteria: Patients aged less than 18 or above 65 ECOG performance status of 2 or more Acute promyelocytic leukaemia Uncontrolled active infection Uncontrolled arrhythmia Altered renal dysfunction with serum creatinine > 1.5 x ULN and/or creatinine clearance < 50 mL/min Significant neurologic (grade > 2) or psychiatric disorder, dementia or seizures Clinical symptoms suggesting active central nervous system leukemia Severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock or disseminated intravascular coagulation Patients with known HIV, Hepatitis B or C infection or history of cirrhosis Patients Significant hepatic dysfunction: Direct bilirubin > 1.5 x upper limit of normal (ULN) for age; ALT or AST > 3 x upper limit of normal (ULN) for age; Lipase > 2.0 x upper limit of normal (ULN) for age Females of childbearing potential must have a negative pregnancy test

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Clofarabine, AraC, mitoxantrone (CLAM)<br>This is the single arm with the intervention using Clofarabine, AraC, Mitoxantrone | Drug: Clofarabine, AraC, mitoxantrone (CLAM)<br>* The combination of clofarabine, cytarabine (Ara-C) and mitoxantrone will be used in patients with AML in first relapse or after failure of first salvage<br>* Other names: CLAM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Remission status will be assessed on day 28 of treatment for the assessment of response rate using standard criteria | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukemia-free survival | This is defined as time (in months) from remission after CLAM regimen to relapse (event), death (censor), HSCT (censor) or latest follow-up (censor). | 2 years | 
| Overall survival | This is defined as the time (in months) from recruitment to death (event) or latest follow-up (censor). | 5 years | 
| Adverse events | Toxicity will be defined using the NCI Common Terminology Criteria for Adverse Events (CTCAE). Data on all toxicities listed will be recorded. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clofarabine, Acute Myeloid Leukemia