Clinical trial NCT03384225: CBA Versus FBA Conditioning Followed by Haploidentical Allogeneic HSCT in Treatment of High Risk and Refractory AML
Official title: CBA Versus FBA Conditioning Followed by Haploidentical Allogeneic HSCT in Treatment of High Risk and Refractory AML
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: High Risk Acute Myeloid Leukemia
Allogeneic Hematopoeitic Stem Cell Transplantation
Keywords: cladribine
fludarabine
relapse
Lead sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Changhai Hospital
name: Xiangya Hospital of Central South University
name: Tongji Hospital
name: Wuhan Union Hospital, China
name: Chengdu PLA General Hospital
name: Tang-Du Hospital
name: Fujian Medical University Union Hospital
First posted: 2017-12-27
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment open labled randomized controlled study
Primary purpose: TREATMENT

Brief summary: Aim: To evaluated if cladribine based conditioning (CBA) could decrease relapse after haploidentical allogeneic HSCT in high risk and refractory AML patients as compared with fludarabine based conditioning regimen(FBA).

Study design: open-labed, prospective, multicenter, randomized control study Number of subjects: 60 each group

Treatment:

CBA group: CBA as HSCT conditioning which including cladribine 5mg/m2 day

-6 to day -2 , busulfan(iv) 3.2mg/kg day-6 to day -3 and cytarabine 2g/m2 day-6 to day -2. FBA group: FBA as HSCT conditioning which including fludarabine 30mg/m2 day -6 to day -2, busulfan(iv) 3.2mg/kg day-6 to day -3 and cytarabine 2g/m2 day-6 to day -2.

Detailed description: Relapse is still the main reason of death for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT), especially for those with high risk and refractory disease. Cladribine and fludarabine are both purine analogs used in treatment of AML. Two studies by the Polish Adult Leukemia Group (PALG) demonstrated that the addition of cladribine to DA (DAC) was associated with an increased complete remission (CR) rate and prolonged overall survival (OS) in the general AML population, with the most prominent effect in patients with unfavorable cytogenetics. Therefore we presume cladribine may more effective in eliminating leukemic cells so that reduce relapse after HSCT. Haploidentical HSCT was the main option for those without HLA matched donors and the number of haploidentical transplants has covered over fifty percent of all allogeneic transplants in China. We designed this study to evaluated if cladribine based conditioning (CBA) could decrease relapse after haploidentical HSCT in high risk and refractory AML patients as compared with fludarabine based conditioning regimen(FBA).

Eligible patients in this study should between 18 to 60 years old with confirmed AML and fulfilled at least one criteria defining high risk or refractory disease.Patients have no HLA matched sibling or unrelated donors but have haploidentical donor. Patients will be excluded if they present any contraindication for HSCT, including respiratory failure, heart failure, liver or kidney function failure et al.

To evaluate if CBA could decrease relapse after haploidentical HSCT in high risk and refractory AML patients as compared with FBA, 120 eligible patients will be randomized to two groups, the CBA group and the FBA group. Patients in the CBA group receive conditioning including cladribine 5mg/m2 day -6 to day -2 , busulfan(iv) 3.2mg/kg day-6 to day -3 and cytarabine 2g/m2 day-6 to day -2. While patients in the FBA group receive conditioning including fludarabine 30mg/m2 day -6 to day -2 , busulfan(iv) 3.2mg/kg day-6 to day-3 and cytarabine 2g/m2 day-6 to day -2. Graft versus host disease(GVHD) prophylactic regimen include ATG 2.5mg/kg d-4 to d-1, cyclosporine A and short term MTX.

Patients will be followed up for 2 years and the primary end point is the cumulative relapse rate at 2 years. The second end points of the study include the overall survival, disease free survival and non-relapse mortality at 2 years.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of AML confirmed by bone marrow cell morphology, immunology, cytogenetics and molecular biology (MICM). Blast crisis of chronic myeloid leukemia (CML) and AML transferred from myelodysplastic syndrome(MDS) or other diseases are also included.
2. AML with high risk cytogenetic abnormals, such as FLT3- ITD, et al.
3. Patients fulfilled at least one of the following criteria defining refractory AML:(1) primary induction failure (PIF) after 2 or more cycles of chemotherapy; (2) first early relapse after a remission duration of fewer than 12 months and refractory to salvage combination chemotherapy; (3) second or subsequent relapse .
4. Have no HLA matched siblings or unrelated donors, but have haploidentical donor. The donor must match the health conditions of hematopoietic stem cell donation (criteria of China Marrow Donor Program) and be willing to donate.
5. Performance status score no more than 2 (ECOG criteria).
6. Adequate organ function as defined by the following criteria:ALT, AST and total serum bilirubin \<2×ULN (upper limit of normal), Serum creatinine and BUN \<1.25×ULN.
7. Adequate cardiac function without acute myocardial infarction, arrhythmia or atrioventricular block, heart failure, active rheumatic heart disease and cardiac dilatation.
8. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.
9. Willingness and ability to comly with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Presence of any condition inappropriate for HSCT.
2. Presence of any fatal disease, including respiratory failure, heart failure, liver or kidney function failure et al.
3. Have no suitable donor.
4. Pregnancy or breast feeding.
5. Current treatment on another clinical trail.
6. Any other condition the investigator judged the patient inappropriate for entry into this study

Primary outcomes:
measure: cumulative relapse rate at 2 year
timeFrame: 2 years
Secondary outcomes:
measure: overall survival at 2 year
timeFrame: 2 years
measure: disease free survival at 2year
timeFrame: 2 years
measure: non-relapse mortality at 2year
timeFrame: 2 years
measure: non-relapse mortality at 100days
timeFrame: 100 days
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai general hospital, Shanghai Jiaotong university school of medicine
state: Shanghai
Study officials:
affiliation: Shanghai General Hospital, Shanghai Jiaotong University School of Medicine
name: Chun Wang, M.D.,Ph. D.
role: STUDY_CHAIR
References:
citation: Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszynska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K; Polish Adult Leukemia Group (PALG). Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia. 2004 May;18(5):989-97. doi: 10.1038/sj.leu.2403336.
citation: Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8. doi: 10.1200/JCO.2011.37.1286. Epub 2012 Apr 16.