Ruxolitinib and Decitabine for High Risk Hematological Malignancies

Ruxolitinib and Decitabine Intensified Conditioning Regimen for Patients With High Risk Hematological Malignancies Underwenting Allogeneic Stem Cell Transplantation

The purpose of this study is to determine the efficacy and safety of Ruxolitinib and Decitabine intensified Conditioning Regimen in Patients with High Risk hematological malignancies undergoing allogeneic peripheral blood stem cell transplantation.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Blood Stem Cell Transplantation
• Intervention / Treatment: Drug: modified By/Cy conditioning regimen intensified by Ruxolitinib and Decitabine

Detailed Description

Allogeneic hematopoietic stem cell transplantation should be offered to eligible patients with high risk hematological malignancies whenever feasible. To further improve the outcome of transplantation patients with high risk hematological malignancies, the investigators developed a modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine. In this study, the investigators tested the efficacy and feasibility of the modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine in Patients with high risk hematological malignancies undergoing allogeneic peripheral blood stem cell transplantation.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Daihong Liu; Phone Number: 86-13681171597; Email: daihongrm@163.com
• Study Contact Backup: Name: Liping Dou; Phone Number: 96-13681207138; Email: lipingruirui@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100853
      • Recruiting
      • Chinese PLA General hospital
      • Contact: Jiang Cao; Phone Number: 01066937166

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Relapsed/refractory acute leukemia with indications for allogeneic hematopoietic stem cell transplantation; High risk acute leukemia with indications for allogeneic hematopoietic stem cell transplantation;
2. Medium to high risk myelodysplastic syndrome, myeloproliferative disease, myelodysplastic syndrome/myeloproliferative disease, Chronic myelomonocytic leukemia;
3. Have matched sibling donors, ≥8/10 HLA matched unrelated donors or haploidentical donors
4. All patients should aged 12 to 65 years;
5. Liver function: ALT and AST≤2.5 times the upper limit of normal , bilirubin≤2 times the upper limit of normal;
6. Renal function: creatinine ≤the upper limit of normal;
7. Patients without any uncontrolled infections , without organ dysfunction or without severe mental illness;
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2;
9. Have signed informed consent.

Exclusion Criteria:

1. pregnant women;
2. Patients with mental illness or other states unable to comply with the protocol;
3. AML patients with t (15;17);

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: Ruxolitinib combined with Decitabine; Ruxolitinib and Decitabine conditioning regimen All recipients in this arm received the modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine. The conditioning regimen for allogeneic hematopoietic stem cell transplantation consist of ruxolitinib (35 mg bid [p.o.], days -15 to -10, diminishing to day -1), decitabine (20 mg/m2/day, days -15 to -10), cytarabine (4 g/m2/day, days -10 to -9 (for unrelated donors or haploidentical donors; and 4 g/m2/day, days -9 for sibling donors)), busulfan (0.8mg/kg, Q6h, days -8 to -6), cyclophosphamide (1.8 g/m2/day, days -5 to -4);carmustine(BCNU)(250mg/m2/day, day -3),

Drug: modified By/Cy conditioning regimen intensified by Ruxolitinib and Decitabine; Day -15 to -14 ： Decitabine 20 mg/m2/day, Ruxolitinib 70mg bid; Day-10： Cytarabine 1.6 g/m2/day CI (only for Haploidentical and unrelated donor), Ruxolitinib 60mg bid; Day- 9： Cytarabine 4g/m2/day CI, Ruxolitinib 60mg bid; Day- 8 to -7： Busulfan 0.8mg/kg Q6h iv, Ruxolitinib 50mg bid; Day-6: Busulfan 0.8mg/kg Q6h iv, Ruxolitinib 40mg bid; Day-5： Cyclophosphamide 1.8 g/m2/day CI, Ruxolitinib 30mg bid; Day-4： Cyclophosphamide 1.8 g/m2/day CI, Ruxolitinib 20mg bid; Day-3： Carmustine 250mg/m2/day iv, Ruxolitinib 10mg bid; Day-2： Ruxolitinib 5mg bid; Day-1： Ruxolitinib 5mg qd; Other Names: Ruxolitinib and Decitabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants relapse as assessed by NCCN (National Comprehensive Cancer Network )criteria	Defined as the proportion of participants whose underlying malignancy relapsed.	365 days after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DFS(disease-free survival )	DFS was defined as survival with no evidence of relapse or progression.	365 days after transplantation
TRM(treatment-related mortality )	Defined as the proportion of subjects who died due to causes other than malignancy relapse.	365 days after transplantation
Number of participants with aGVHD as assessed by acute graft versus host disease grading criteria (refer to Glucksberg criteria)	Defined as the proportion of participants who developed acute GVHD.	100 days after transplantation
Number of participants with cGVHD as assessed by chronic graft versus host disease grading criteria (refer to NIH criteria)	Defined as the proportion of participants who developed chronic GVHD.	365 days after transplantation
OS(overall survival )	OS was defined as the time from transplantation to death due to any cause.	365 days after transplantation
GRFS (GVHD free, relapse free survival)	GVHD-free, relapse-free survival (GRFS) was defined as survival with no evidence of grade III-IV acute GVHD or cGVHD requiring immunosuppressive treatment, and without disease recurrence or death from any cause during the first year after transplantation.	365 days after transplantation
infection rate	Defined as the proportion of participants who developed all kinds of infection.	365 days after transplantation

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Investigators: Principal Investigator: Daihong Liu, Chinese PLA General hospital

Publications and helpful links

General Publications

• Karjalainen R, Pemovska T, Popa M, Liu M, Javarappa KK, Majumder MM, Yadav B, Tamborero D, Tang J, Bychkov D, Kontro M, Parsons A, Suvela M, Mayoral Safont M, Porkka K, Aittokallio T, Kallioniemi O, McCormack E, Gjertsen BT, Wennerberg K, Knowles J, Heckman CA. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML. Blood. 2017 Aug 10;130(6):789-802. doi: 10.1182/blood-2016-02-699363. Epub 2017 Jun 15.
• Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, Otto GA, Yelensky R, Hricik T, McKenney AS, Chiosis G, Chung YR, Pandey S, van den Brink MR, Armstrong SA, Dogan A, Intlekofer A, Manshouri T, Park CY, Verstovsek S, Rapaport F, Stephens PJ, Miller VA, Levine RL. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5401-10. doi: 10.1073/pnas.1407792111. Epub 2014 Dec 2.
• Delgado-Martin C, Meyer LK, Huang BJ, Shimano KA, Zinter MS, Nguyen JV, Smith GA, Taunton J, Winter SS, Roderick JR, Kelliher MA, Horton TM, Wood BL, Teachey DT, Hermiston ML. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. Leukemia. 2017 Dec;31(12):2568-2576. doi: 10.1038/leu.2017.136. Epub 2017 May 9.
• Venugopal S, Bar-Natan M, Mascarenhas JO. JAKs to STATs: A tantalizing therapeutic target in acute myeloid leukemia. Blood Rev. 2020 Mar;40:100634. doi: 10.1016/j.blre.2019.100634. Epub 2019 Oct 25.
• Ding YY, Stern JW, Jubelirer TF, Wertheim GB, Lin F, Chang F, Gu Z, Mullighan CG, Li Y, Harvey RC, Chen IM, Willman CL, Hunger SP, Li MM, Tasian SK. Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure. Haematologica. 2018 Sep;103(9):e427-e431. doi: 10.3324/haematol.2018.192088. Epub 2018 May 17. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 30, 2025

Study Registration Dates

• First Submitted: October 3, 2020
• First Submitted That Met QC Criteria: October 3, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Actual): October 20, 2020
• Last Update Submitted That Met QC Criteria: October 19, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: S2020-297-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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