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

Core Binding Factor Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05404516
• Other study ID #: Sorafenib-CBF AML-2022
• Status: Recruiting
• Phase: Phase 2
• Start date: January 1, 2020
• Est. completion date: December 31, 2023

Study information

• Verified date: May 2022
• Source: Nanfang Hospital of Southern Medical University
• Contact: Pengcheng Shi
• Phone: +86-020-62787883
• Email: shpch283[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: December 31, 2023
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Core Binding Factor Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
China	Department of Hematology,Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong

Sponsors (7)

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

Country where clinical trial is conducted

China, 

References & Publications (3)

Paschka P, Schlenk RF, Weber D, Benner A, Bullinger L, Heuser M, Gaidzik VI, Thol F, Agrawal M, Teleanu V, Lübbert M, Fiedler W, Radsak M, Krauter J, Horst HA, Greil R, Mayer K, Kündgen A, Martens U, Heil G, Salih HR, Hertenstein B, Schwänen C, Wulf G, Lange E, Pfreundschuh M, Ringhoffer M, Girschikofsky M, Heinicke T, Kraemer D, Göhring G, Ganser A, Döhner K, Döhner 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. — View Citation

Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner 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. — View Citation

Rücker FG, Agrawal M, Corbacioglu A, Weber D, Kapp-Schwoerer S, Gaidzik VI, Jahn N, Schroeder T, Wattad M, Lübbert M, Koller E, Kindler T, Götze 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, Döhner H, Döhner 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CMR (Complete Molecular Remission)	CMR in BM after 4 cycles of chemotherapies	1 year
Secondary	Overall survival		3 year
Secondary	Leukemia-free survival		3 year
Secondary	Cumulative incidence of relapse		3 year
Secondary	Adverse effects		1 year