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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03235973
Recruitment Status : Recruiting
First Posted : August 1, 2017
Last Update Posted : June 28, 2018
Information provided by (Responsible Party):
Institut Paoli-Calmettes

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.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Leukemia, Lymphoblastic, Acute Drug: Fludarabine-Cladribine-Busulfan conditioning regimen Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes
Actual Study Start Date : April 28, 2018
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2021

Arm Intervention/treatment
Experimental: Fludarabine-Cladribine-Busulfan conditioning regimen Drug: Fludarabine-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

Primary Outcome Measures :
  1. 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) [ Time Frame: 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 Outcome Measures :
  1. Cumulative incidence of acute Graft versus host disease [ Time Frame: 100 days ]
    Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification

  2. Cumulative incidence of chronic Graft versus host disease [ Time Frame: 1 year ]
    Cumulative incidence of chronic Graft versus host disease according to NIH classification

  3. Cumulative incidence of relapse [ Time Frame: 1 year ]
    Cumulative incidence of relapse at 1 year

  4. Cumulative incidence of Non Relapse Mortality [ Time Frame: 100 days, 1 year ]
    Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03235973

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Contact: Dominique Genre, MD +33491223778
Contact: Jihane Pakradouni, PharmD, PhD +33491223778

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Institut Paoli-Calmettes Recruiting
Marseille, Bouches-du-Rhône, France, 13009
Contact: Dominique Genre, MD    +33491223778   
Principal Investigator: Raynier Devillier, MD,PhD         
Sponsors and Collaborators
Institut Paoli-Calmettes
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Principal Investigator: Raynier Devillier, MD,PhD Institut Paoli-Calmettes

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Responsible Party: Institut Paoli-Calmettes Identifier: NCT03235973     History of Changes
Other Study ID Numbers: CEREAL-IPC 2016-010
First Posted: August 1, 2017    Key Record Dates
Last Update Posted: June 28, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut Paoli-Calmettes:
refractory acute leukemia
refractory myelodysplastic syndrome
cladribine dose escalation
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Fludarabine phosphate
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists