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Combination of Sorafenib With Standard Therapy in Newly Diagnosed Adult CBF AML

Primary Purpose

Core Binding Factor Acute Myeloid Leukemia

Status

Recruiting

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Sorafenib

Idarubicin

Cytarabine

About this trial

This is an interventional treatment trial for Core Binding Factor Acute Myeloid Leukemia focused on measuring Core Binding Factor Acute Myeloid Leukemia, Sorafenib, CMR (Complete Molecular Remission)

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have an unequivocal diagnosis of de novo-CBF AML, prior to start therapy, documented by rearrangement of Core Binding Factor (CBF) genes, namely RUNX1/RUNX1T1 and CBFB/MYH11.
Age 18 to 65 years old with ECOG performance status 0-2.
Sign informed consent form, have the ability to comply with study and follow-up procedures.
Patients must have Total Bilirubin ≤ 1.5 x ULN, and AST or ALT ≤ 2.5 x ULN.
Patients must have Serum Creatinine ≤ 1.5 x ULN.
Women of child-bearing potential must have a negative pregnancy test before starting the protocol.

Exclusion Criteria:

Prior therapy for AML with the following exceptions:
1. emergency leukapheresis
2. emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days.
Central nervous system involvement.
Presence of any uncontrolled bacterial, viral or fungal infection.
Known human immunodeficiency virus (HIV) positive.
An active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Patients whose disease is controlled under antiviral therapy should not be excluded.
Presence of other active malignancies.
QTc > 470 msec (Bazett formula) on screening ECG.
Presence of significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to:
1. Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to randomization
2. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia
3. Uncontrolled hypertension
4. Taking medications that are known to be associated with Torsades de Pointes.
History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment.
Intolerance to sorafenib, namely persistence of sorafenib-related adverse events despite supportive treatment, persistence or recurrence of adverse events after dose interruption or dose reduction of sorafenib, or both of these.

Sites / Locations

Department of Hematology,Nanfang Hospital, Southern Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Sorafenib

Standard therapy

Arm Description

Induction cycle(s): IA3+7. Patients will receive sorafenib 400 mg BID on days 8-21. Consolidation Cycle 1: IA3+3. Patients will receive sorafenib 400 mg BID on days 1-21. Consolidation Cycles 2-4: MDAC. Patients will receive sorafenib 400 mg BID on days 1-21. Maintenance therapy: Single agent sorafenib 400 mg BID for one year.

Induction cycle(s): IA3+7. Consolidation Cycle 1: IA3+3. Consolidation Cycles 2-4: MDAC.

Outcomes

Primary Outcome Measures

CMR (Complete Molecular Remission)

CMR in BM after 4 cycles of chemotherapies

Secondary Outcome Measures

Overall survival

Leukemia-free survival

Cumulative incidence of relapse

Adverse effects

Full Information

NCT ID

NCT05404516

First Posted

May 31, 2022

Last Updated

May 31, 2022

Sponsor

Nanfang Hospital, Southern Medical University

Collaborators

Guangzhou First People's Hospital, Guangzhou Panyu Central Hospital, Institute of Hematology & Blood Diseases Hospital, China, Peking University People's Hospital, Shenzhen Hospital of Southern Medical University, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

1. Study Identification

Unique Protocol Identification Number

NCT05404516

Brief Title

Combination of Sorafenib With Standard Therapy in Newly Diagnosed Adult CBF AML

Official Title

Prospective Evaluation of Sorafenib Combined With Standard Therapy in Newly Diagnosed Adult Core-binding Factor Acute Myeloid Leukemia: an Open-label , Randomised Controlled, Multicenter Phase II Trial

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 1, 2020 (Actual)

Primary Completion Date

August 31, 2022 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Nanfang Hospital, Southern Medical University

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Core-binding factor acute myeloid leukemia accounts for 10-15% of AML and is categorized as favorable-risk AML. However, the 5-year CIR was up to 40% in this group of patients. Emerging data show that a high frequency of mutations and/or high expression of KIT in CBF AML. Sorafenib is a multitargeted TKI, thus the purpose of this study is to evaluate the safety and efficacy of sorafenib combined with standard therapy in CBF AML.

Detailed Description

Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and accounts for 10-15% of AML. Because of the high CR rate of nearly 90% and a 5-year OS of almost 50%, CBF-AML is categorized as favorable-risk AML. However, the 5-year cumulative incidence of relapse (CIR) was up to 40% in this group of patients after high-dose cytarabine consolidation following CR. Therefore, more effective therapeutic approaches are needed. Emerging data show that a high frequency of mutations and/or high expression of KIT in CBF AML likely result in aberrant tyrosine kinase activity, leukemia cell growth and survival, and treatment resistance. Thus, pharmacologic inhibition of KIT would lead to significant antileukemia activity if combined with an optimized chemotherapy regimen in patients with CBF AML. Recent mechanistic findings also support the potential clinical benefit of KIT inhibition in CBF AML. Sorafenib is a first-generation type-II multitargeted tyrosine kinase receptor inhibitor (TKI) that suppresses various signaling pathways associated with the development of AML, such as RTK (FLT3, c-KIT), RAS/RAF, vascular endothelial growth factor (VEGF) receptor. The purpose of this study is to evaluate the safety and efficacy of sorafenib combined with standard therapy in CBF AML.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Core Binding Factor Acute Myeloid Leukemia

Keywords

Core Binding Factor Acute Myeloid Leukemia, Sorafenib, CMR (Complete Molecular Remission)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

88 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sorafenib

Arm Type

Experimental

Arm Description

Arm Title

Standard therapy

Arm Type

Active Comparator

Arm Description

Induction cycle(s): IA3+7. Consolidation Cycle 1: IA3+3. Consolidation Cycles 2-4: MDAC.

Intervention Type

Drug

Intervention Name(s)

Sorafenib

Intervention Description

Induction cycle(s): 400 mg BID on days 8-21. Consolidation cycles 1-4: 400 mg BID on days 1-21. Maintenance therapy: 400 mg BID for one year.

Intervention Type

Drug

Intervention Name(s)

Idarubicin

Intervention Description

Induction cycle(s): 12 mg/m2/day on days 1-3. Consolidation cycle 1: 8 mg/m2/day administered on days 1-3.

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Intervention Description

Induction cycle(s): 100 mg/m2 by continuous IV infusion for 24 hours on days 1-7. Consolidation cycles 1-4: 2 g/m2/12h on days 1-3.

Primary Outcome Measure Information:

Title

CMR (Complete Molecular Remission)

Description

CMR in BM after 4 cycles of chemotherapies

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Overall survival

Time Frame

3 year

Title

Leukemia-free survival

Time Frame

3 year

Title

Cumulative incidence of relapse

Time Frame

3 year

Title

Adverse effects

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have an unequivocal diagnosis of de novo-CBF AML, prior to start therapy, documented by rearrangement of Core Binding Factor (CBF) genes, namely RUNX1/RUNX1T1 and CBFB/MYH11. Age 18 to 65 years old with ECOG performance status 0-2. Sign informed consent form, have the ability to comply with study and follow-up procedures. Patients must have Total Bilirubin ≤ 1.5 x ULN, and AST or ALT ≤ 2.5 x ULN. Patients must have Serum Creatinine ≤ 1.5 x ULN. Women of child-bearing potential must have a negative pregnancy test before starting the protocol. Exclusion Criteria: Prior therapy for AML with the following exceptions: emergency leukapheresis emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days. Central nervous system involvement. Presence of any uncontrolled bacterial, viral or fungal infection. Known human immunodeficiency virus (HIV) positive. An active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Patients whose disease is controlled under antiviral therapy should not be excluded. Presence of other active malignancies. QTc > 470 msec (Bazett formula) on screening ECG. Presence of significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to: Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to randomization History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia Uncontrolled hypertension Taking medications that are known to be associated with Torsades de Pointes. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment. Intolerance to sorafenib, namely persistence of sorafenib-related adverse events despite supportive treatment, persistence or recurrence of adverse events after dose interruption or dose reduction of sorafenib, or both of these.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Pengcheng Shi

Phone

+86-020-62787883

shpch283@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Qifa Liu

Organizational Affiliation

Nanfang Hospital, Southern Medical University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Hematology,Nanfang Hospital, Southern Medical University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510515

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pengcheng Shi

shpch283@163.com

First Name & Middle Initial & Last Name & Degree

Qifa Liu

12. IPD Sharing Statement

Citations:

PubMed Identifier

31554635

Citation

Rucker FG, Agrawal M, Corbacioglu A, Weber D, Kapp-Schwoerer S, Gaidzik VI, Jahn N, Schroeder T, Wattad M, Lubbert M, Koller E, Kindler T, Gotze K, Ringhoffer M, Westermann J, Fiedler W, Horst HA, Greil R, Schroers R, Mayer K, Heinicke T, Krauter J, Schlenk RF, Thol F, Heuser M, Ganser A, Bullinger L, Paschka P, Dohner H, Dohner K. Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group. Blood. 2019 Nov 7;134(19):1608-1618. doi: 10.1182/blood.2019001425.

Results Reference

background

PubMed Identifier

29720733

Citation

Paschka P, Schlenk RF, Weber D, Benner A, Bullinger L, Heuser M, Gaidzik VI, Thol F, Agrawal M, Teleanu V, Lubbert M, Fiedler W, Radsak M, Krauter J, Horst HA, Greil R, Mayer K, Kundgen A, Martens U, Heil G, Salih HR, Hertenstein B, Schwanen C, Wulf G, Lange E, Pfreundschuh M, Ringhoffer M, Girschikofsky M, Heinicke T, Kraemer D, Gohring G, Ganser A, Dohner K, Dohner H. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018 Jul;32(7):1621-1630. doi: 10.1038/s41375-018-0129-6. Epub 2018 Apr 17.

Results Reference

background

PubMed Identifier

26549589

Citation

Rollig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Kramer A, Schafer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hanel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanss C, Repp R, Heits F, Durk H, Hase J, Klut IM, Illmer T, Bornhauser M, Schaich M, Parmentier S, Gorner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, Ehninger G; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 Dec;16(16):1691-9. doi: 10.1016/S1470-2045(15)00362-9. Epub 2015 Nov 6.

Results Reference

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Combination of Sorafenib With Standard Therapy in Newly Diagnosed Adult CBF AML

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