Leukemia, Lymphoblastic, Acute, Leukemia, Myeloid, Acute
Conditions
Keywords
refractory acute leukemia, refractory myelodysplastic syndrome, cladribine dose escalation
Brief summary
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.
Interventions
DRUGFludarabine-Cladribine-Busulfan conditioning regimen
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
Sponsors
Institut Paoli-Calmettes
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 30 days after Allo-HSCT | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative incidence of acute Graft versus host disease | 100 days | Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification |
| Cumulative incidence of chronic Graft versus host disease | 1 year | Cumulative incidence of chronic Graft versus host disease according to NIH classification |
| Cumulative incidence of relapse | 1 year | Cumulative incidence of relapse at 1 year |
| Cumulative incidence of Non Relapse Mortality | 100 days, 1 year | Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT |
Countries
France
Contacts
Primary ContactDominique Genre, MD
Backup ContactJihane Pakradouni, PharmD, PhD
Outcome results
None listed