Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes

Study Overview
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Brief Summary
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The investigators focused on patients with refractory acute leukemia or MDS and designed a phase 1 trial of escalated cladribine doses in the Cla-Flu-Bu RTC regimen using PK-guided myeloablative busulfan doses. This scheme allows combining different optimization of RTC experienced over years (Flu-Bu RTC, PK-guided myeloablative busulfan doses, a second purine analog cladribine) to approach a specific platform to treat refractory diseases.

Official Title
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Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes

Conditions
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Leukemia, Myeloid, Acute, Leukemia, Lymphoblastic, Acute

Intervention / Treatment
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* Drug: Fludarabine-Cladribine-Busulfan conditioning regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 ECOG 0 or 1 Acute leukemia (AML or ALL) without criteria for CR or high risk MDS without criteria for CR Availability of a donor among following oHLA identical sibling oHaploidentical donor o10/10 or 9/10 allele-level HLA matched unrelated donor Signed informed consent Patient affiliated to the national Social Security regimen or beneficiary of this regimen Exclusion Criteria: Contraindication for Allo-HSCT Cord blood Allo-HSCT Current active disease or positive serology for HIV, and/or HCV with detectable viremia and/ or HBV with positive Hbs Antigen. Renal failure with creatinine clearance < 30 ml/ min Decompensated haemolytic anaemia Hypersensitivity to an active substance or to any of the excipients Acute urinary infection Pre-existing haemorrhagic cystitis Woman of childbearing potential not using an effective contraception . Pregnant or lactating women Any serious concurrent uncontrolled medical disorder Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: Fludarabine-Cladribine-Busulfan conditioning regimen<br> | Drug: Fludarabine-Cladribine-Busulfan conditioning regimen<br>* Conditioning regimen will be performed from day -6 to day -2 and contains: Fludarabine 10 mg/m²/d during 5 days (day-6 to day-2). Cladribine during 5 days (day-6 to day-2) at one the following define dose level: Dose 1: 10 mg/m²/d Dose 2: 15 mg/m²/d Dose 3: 20 mg/m²/d Dose 4: 25 mg/m²/d IV busulfan will be given on day-6 using fixed dose as following: If age ≤ 60 years: starting dose of 130 mg/m² If age > 60 years: starting dose of 100 mg/m² No busulfan will be administered at day-5, allowing the pharmacokinetic (PK) analyses . Subsequent infusion of IV busulfan will be performed from day-4 to day-2 at the dose recommended by PK analyses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| estimation of the maximal tolerable dose,if any,and recommended phase II dose of cladribine administered as in combination with fludarabine and PK-guided IV busulfan prior Allo-HSCT for refractory acute leukemia and myelodysplastic syndrome (MDS) | Occurrence ratio of dose-limiting toxicity defined as any grade ≥ 3 toxicity according to CTCAE (version 4.03 ) attributable to conditioning regimen (extra-medullary toxicity), considered to be related or probably related to the Cla-Fu-Bu RTC by the investigator. | 30 days after Allo-HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of acute Graft versus host disease | Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification | 100 days | 
| Cumulative incidence of chronic Graft versus host disease | Cumulative incidence of chronic Graft versus host disease according to NIH classification | 1 year | 
| Cumulative incidence of relapse | Cumulative incidence of relapse at 1 year | 1 year | 
| Cumulative incidence of Non Relapse Mortality | Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT | 100 days, 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory acute leukemia, refractory myelodysplastic syndrome, cladribine dose escalation