Sorafenib Plus 5-Azacitidine Initial Therapy of Patients With Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MS) With FLT3-ITD Mutation

NCT02196857 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2014-0076NCI-2014-01702
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to learn if 5-azacitidine and sorafenib can help to control the disease in patients with Acute Myeloid Leukemia (AML) and high risk Myelodisplastic Syndrome (MDS) with FLT3-ITD mutation. The safety of this drug combination will also be studied.

Conditions

Leukemia

Keywords

Leukemia; Acute myeloid leukemia; AML; High risk myelodysplastic syndrome; MDS; FLT3-ITD mutation; Azacytidine; 5-Azacytidine; 5-AZA; Vidaza; 5-AZC; AZA-CR; Ladakamycin; NSC-102816; Sorafenib; Nexavar; BAY 43-9006

Outcome Measures

Primary Outcomes (1)

• Participants With a Response CR + PR + CRi

  Criteria for response per the International Working Group for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Complete Response (CR) was defined as \</= 5% blasts in the bone marrow (BM) with peripheral blood (PB) demonstrating greater thatn 1x10\^9/L platelets with no detectable extramedullary disease. CR with incomplete recovery of PB counts (CRi) is the above criteria but neutrophil or platelet counts less than the stated values. Partial Response (PR) required all of the hematologic values for a CR but with a reduction of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.

  After 3, 28 day cycles

Secondary Outcomes (1)

• Toxicity Profile of Azacytidine and Sorafenib

  After 3, 28 day cycles

Study Arms (1)

Azacytidine + Sorafenib

EXPERIMENTAL

Azacitidine 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) daily for 7 days per 28 day cycle. Sorafenib administered orally at a dose of 400 mg twice daily every day continuously.

Drug: Azacytidine; Drug: Sorafenib

Interventions

Azacytidine DRUG

75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle.

Also known as: 5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816

Azacytidine + Sorafenib

Sorafenib DRUG

400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.

Also known as: Nexavar, BAY 43-9006

Azacytidine + Sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with untreated AML (\> or equal to 20% blasts in bone marrow and/or peripheral blood) or high risk MDS (\> or equal to 10% blasts in bone marrow). A. Patients with AML and history of MDS who have received prior therapy with a hypomethylating agent (including azacytidine) and/or with lenalidomide for prior MDS are eligible if the treating physician feels that participation in the study is in the patients' best interest. B. Patients should have molecular evidence of the presence of FLT3-ITD mutation with a molecular burden of at least 10%.
• Age \> or equal to 60 years; patients younger than 60 who are unsuitable for or unwilling to receive standard cytotoxic chemotherapy are also eligible to be enrolled.
• Eastern Cooperative Oncology Group (ECOG) Performance Status \< or equal 2.
• Adequate liver (bilirubin \< or equal to 1.5 x ULN, Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) \< or equal to 2.5 x ULN and Alkaline phosphatase \< or equal to 4 x ULN if not related to leukemic disease) and renal (creatinine \< or equal to 1.5 x ULN) function.
• Patients must provide written informed consent.
• Patients must have been off therapy for MDS for 2 weeks prior to entering this study, and must have recovered from the toxic effects of that therapy to at least grade 1, unless there is evidence of rapidly progressive disease. Use of hydroxyurea (any dose) or ara-C (up to 1 g/m\^2 X 2 doses) for patients with rapidly proliferative disease is allowed before the start of study therapy; these should be stopped for 24 hours prior to the initiation of azacitidine and sorafenib.
• Women of childbearing potential should be advised to avoid becoming pregnant with an adequate method of contraception (barrier or hormonal methods) and men should be advised to not father a child while receiving treatment with azacitidine. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below: Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Men should use adequate birth control for at least 30 days after the last administration of sorafenib. Post-menopausal women (defined as no menses for at least one year) and surgically sterilized women are not required to undergo a pregnancy test. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study.
• \. Continued: Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
• International Normalized Ratio (INR) \< or equal to 1.5. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored weekly, or as defined by the local standard of care, until INR is stable.

You may not qualify if:

• Nursing and pregnant females.
• Patients with acute promyelocytic leukemia are excluded.
• Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.
• Patients with known severe impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sorafenib.
• Patients with any other known disease (except carcinoma in-situ) or concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months and uncontrolled hypertension, chronic renal disease (creatinine clearance \< 20 ml/min using the Cockcroft and Gault formula), or active uncontrolled infection) which could compromise participation in the study.
• Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis (B or C).
• Patients who have had any major surgical procedure within 28 days prior to Day 1.
• Patients unwilling or unable to comply with the protocol.
• Cardiac disease: Congestive heart failure \> class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
• Uncontrolled hypertension defined as systolic blood pressure \> 150? mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
• Active clinically serious infection \> CTCAE v4, Grade 2 not controlled with antibiotics.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event \> or equal to CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.
• Any other hemorrhage/bleeding event \> or equal to CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.
• Serious non-healing wound, ulcer, or bone fracture.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Bayer: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Ohanian M, Garcia-Manero G, Levis M, Jabbour E, Daver N, Borthakur G, Kadia T, Pierce S, Burger J, Richie MA, Patel K, Andreeff M, Estrov Z, Cortes J, Kantarjian H, Ravandi F. Sorafenib Combined with 5-azacytidine in Older Patients with Untreated FLT3-ITD Mutated Acute Myeloid Leukemia. Am J Hematol. 2018 Sep;93(9):1136-1141. doi: 10.1002/ajh.25198. Epub 2018 Aug 31.

  PMID: 30028037 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Acute

Interventions

Azacitidine; Sorafenib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Results Point of Contact

• Title: Ravandi-Kashani,Farhad MD./Professor
• Organization: The University of Texas MD Anderson Cancer Center

fravandi@mdanderson.org

713-745-0394

Study Officials

• Farhad Ravandi-Kashani, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 18, 2014
• First Posted: July 22, 2014
• Study Start: February 6, 2015
• Primary Completion: November 27, 2018
• Study Completion: November 27, 2018
• Last Updated: January 14, 2020
• Results First Posted: January 6, 2020

Record last verified: 2020-01

Locations

US (1)