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

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.

Study Overview

• Status: Unknown
• Conditions: Leukemia, Myeloid, Acute; Leukemia, Lymphoblastic, Acute
• Intervention / Treatment: Drug: Fludarabine-Cladribine-Busulfan conditioning regimen

• Study Type: Interventional
• Enrollment (Anticipated): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13009
      • Recruiting
      • Institut Paoli-Calmettes
      • Principal Investigator: Raynier Devillier, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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/dDose 2: 15 mg/m²/dDose 3: 20 mg/m²/dDose 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/m²If 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

What is the study measuring?

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 relapse	Cumulative incidence of relapse at 1 year	1 year
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 Non Relapse Mortality	Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT	100 days, 1 year

Collaborators and Investigators

• Sponsor: Institut Paoli-Calmettes

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2018
• Primary Completion (Anticipated): April 1, 2020
• Study Completion (Anticipated): April 1, 2021

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: July 31, 2017
• First Posted (Actual): August 1, 2017

Study Record Updates

• Last Update Posted (Actual): June 28, 2018
• Last Update Submitted That Met QC Criteria: June 26, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: refractory acute leukemia; refractory myelodysplastic syndrome; cladribine dose escalation
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia, Lymphoid; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Fludarabine; Busulfan; Cladribine
• Other Study ID Numbers: CEREAL-IPC 2016-010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No