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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Core Binding Factor Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Sorafenib; Drug: Idarubicin; Drug: Cytarabine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 88
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pengcheng Shi; Phone Number: +86-020-62787883; Email: shpch283@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Recruiting
      • Department of Hematology,Nanfang Hospital, Southern Medical University
      • Contact: Pengcheng Shi; Email: shpch283@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sorafenib; 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.	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.; Drug: Idarubicin; Induction cycle(s): 12 mg/m2/day on days 1-3. Consolidation cycle 1: 8 mg/m2/day administered on days 1-3.; Drug: 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.
Active Comparator: Standard therapy; Induction cycle(s): IA3+7. Consolidation Cycle 1: IA3+3. Consolidation Cycles 2-4: MDAC.	Drug: Idarubicin; Induction cycle(s): 12 mg/m2/day on days 1-3. Consolidation cycle 1: 8 mg/m2/day administered on days 1-3.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMR (Complete Molecular Remission)	CMR in BM after 4 cycles of chemotherapies	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	3 year
Leukemia-free survival	3 year
Cumulative incidence of relapse	3 year
Adverse effects	1 year

Collaborators and Investigators

• Sponsor: Nanfang Hospital of Southern Medical University
• Collaborators: Peking University People's Hospital; Guangzhou First People's Hospital; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; Institute of Hematology & Blood Diseases Hospital; Guangzhou Panyu Central Hospital; Shenzhen Hospital of Southern Medical University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: May 31, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Actual): June 3, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Sorafenib; Core Binding Factor Acute Myeloid Leukemia; CMR (Complete Molecular Remission)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Sorafenib; Cytarabine; Idarubicin
• Other Study ID Numbers: Sorafenib-CBF AML-2022

Drug and device information, study documents

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