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

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02196857
• Collaborator: Bayer (Industry)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 45.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Azacytidine; Drug: Sorafenib	Phase 2

Detailed Description

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive 5-azacitidine either as an injection under the skin or by vein on Days 1-7 of each 28-day cycle. If by vein, the infusion will take about 10-40 minutes.

You will take sorafenib by mouth 2 times a day about 12 hours apart, with at least 1 cup (8 ounces) of water on an empty stomach, every day. If you vomit a dose, do not make it up. You should wait and take your next scheduled dose.

Each study cycle may last a little longer than 28 days, depending on how you are doing.

Study Visits:

Each week, blood (about 1 tablespoon) will be drawn for routine tests.

Each week for the first 6 weeks, and then as often as your doctor thinks it is needed, you will have your blood pressure measured.

Before each cycle, you will have a physical exam.

Before every 2-4 cycles, you will have a bone marrow aspirate to check the status of the disease.

Length of Study:

You may continue taking the study drugs for as long as your doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse or intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

After you have stopped taking the study drugs, the following tests and procedures will be performed:

• You will have a physical exam.

• You will have a bone marrow aspirate to check the status of disease.

• Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

After your end-of-study visit, you will return to the clinic every 3 months and have the following tests and procedures:

• You will have a physical exam.

• Blood (about 2 tablespoons) will be drawn for routine tests.

This is an investigational study. Sorafenib is FDA approved and commercially available for the treatment of kidney cancer and liver cancer. 5-azacitidine is FDA approved for the treatment of MDS, but combining it with sorafenib is investigational. The study doctor can tell you how the study drugs are designed to work.

Up to 52 participants will be enrolled in this study. All will take part at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome With FLT3-ITD Mutation
• Actual Study Start Date: Feb 6, 2015
• Actual Primary Completion Date: Nov 27, 2018
• Actual Study Completion Date: Nov 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azacytidine + Sorafenib 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; 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle.; Other Names: 5-Azacytidine 5-AZA Vidaza 5-AZC AZA-CR Ladakamycin NSC-102816 ; Drug: Sorafenib; 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.; Other Names: Nexavar BAY 43-9006

Outcome Measures

Primary Outcome Measures

1. Participants With a Response CR + PR + CRi [After 3, 28 day cycles]

   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.

Secondary Outcome Measures

1. Toxicity Profile of Azacytidine and Sorafenib [After 3, 28 day cycles]

   Severity of toxicities graded according to the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0. Standard reporting guidelines followed for adverse events. Safety data summarized by category, severity and frequency.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 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%.

2. 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.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status < or equal 2.

4. 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.

5. Patients must provide written informed consent.

6. 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.

7. 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.

8. 1. 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.

9. 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.

10. 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.

Exclusion Criteria:

1. Nursing and pregnant females.

2. Patients with acute promyelocytic leukemia are excluded.

3. Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.

4. Patients with known severe impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sorafenib.

5. 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.

6. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis (B or C).

7. Patients who have had any major surgical procedure within 28 days prior to Day 1.

8. Patients unwilling or unable to comply with the protocol.

9. 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.

10. Uncontrolled hypertension defined as systolic blood pressure > 150? mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.

11. Active clinically serious infection > CTCAE v4, Grade 2 not controlled with antibiotics.

12. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

13. Pulmonary hemorrhage/bleeding event > or equal to CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.

14. Any other hemorrhage/bleeding event > or equal to CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.

15. Serious non-healing wound, ulcer, or bone fracture.

16. Evidence of bleeding diathesis or coagulopathy within the past 6 months.

17. Known or suspected allergy to sorafenib or any agent given in the course of this trial.

18. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results including known non-compliance issues on study trials.

19. Use of strong CYP3A4 inducer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Bayer

Investigators

• Principal Investigator: Farhad Ravandi-Kashani, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 9, 2015

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT02196857
• Other Study ID Numbers: 2014-0076; NCI-2014-01702
• First Posted: Jul 22, 2014
• Last Update Posted: Jan 14, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: 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
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Azacitidine; Sorafenib

Study Results

Participant Flow

Recruitment Details	Recruitment Period: February 2015 - February 2018

Arm/Group Title	Azacytidine + Sorafenib
Arm/Group Description	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. Azacytidine: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. Sorafenib: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Azacytidine + Sorafenib
Arm/Group Description	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. Azacytidine: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. Sorafenib: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	16 100%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	75
Sex: Female, Male (Count of Participants)
Female	3 18.8%
Male	13 81.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 6.3%
White	13 81.3%
More than one race	0 0%
Unknown or Not Reported	1 6.3%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Participants With a Response CR + PR + CRi
Description	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.
Time Frame	After 3, 28 day cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azacytidine + Sorafenib
Arm/Group Description	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. Azacytidine: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. Sorafenib: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
Measure Participants	16
Complete Response (CR)	4 25%
Partial Response (PR)	1 6.3%
CR with incomplete platelet recovery (CRi)	4 25%

2. Secondary Outcome

Title	Toxicity Profile of Azacytidine and Sorafenib
Description	Severity of toxicities graded according to the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0. Standard reporting guidelines followed for adverse events. Safety data summarized by category, severity and frequency.
Time Frame	After 3, 28 day cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azacytidine + Sorafenib
Arm/Group Description	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. Azacytidine: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. Sorafenib: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
Measure Participants	6
Diarrhea	4 25%
Dyspnea	2 12.5%
Fatigue	5 31.3%
Febrile Neutropenia	4 25%
Nausea	2 12.5%
Pain	2 12.5%
Rash/Desquamation	2 12.5%

Adverse Events

Time Frame	Up to three years
Arm/Group Title	Azacytidine + Sorafenib
Arm/Group Description	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. Azacytidine: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. Sorafenib: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
All Cause Mortality
	Azacytidine + Sorafenib
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	Azacytidine + Sorafenib
	Affected / at Risk (%)	# Events
Total	14/16 (87.5%)
Blood and lymphatic system disorders
Cardiac Triponin Increase	1/16 (6.3%)	1
Intracranial Hemorrhage	1/16 (6.3%)	1
Thrombocytopenia	1/16 (6.3%)	1
Cardiac disorders
Acute Heart Failure	1/16 (6.3%)	1
Gastrointestinal disorders
Colitis	2/16 (12.5%)	4
Dehydration	1/16 (6.3%)	1
Intestine Obstruction	1/16 (6.3%)	1
General disorders
Facial Pain/Dental	1/16 (6.3%)	1
Fatigue	1/16 (6.3%)	2
Fever	1/16 (6.3%)	1
Infections and infestations
Cellulitis	1/16 (6.3%)	2
Febrile Neutropenia	5/16 (31.3%)	8
Urinary Tract Infection	2/16 (12.5%)	2
Infection	1/16 (6.3%)	1
Lung Infection	5/16 (31.3%)	12
Sepsis	1/16 (6.3%)	1
Skin Infection	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/16 (6.3%)	1
Nervous system disorders
Seizure	1/16 (6.3%)	1
Stroke	1/16 (6.3%)	1
Syncope	1/16 (6.3%)	1
Tremor	1/16 (6.3%)	1
Renal and urinary disorders
Acute Kidney failure	1/16 (6.3%)	1
generalized edema	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/16 (6.3%)	1
Dyspnea	2/16 (12.5%)	2
Laryngeal Hemorrhage	1/16 (6.3%)	1
Laryngeal Inflammation	2/16 (12.5%)	2
Vascular disorders
Hypotnesion	4/16 (25%)	4
Other (Not Including Serious) Adverse Events
	Azacytidine + Sorafenib
	Affected / at Risk (%)	# Events
Total	6/16 (37.5%)
Eye disorders
Watery eye	1/16 (6.3%)	1
Gastrointestinal disorders
Diarrhea	4/16 (25%)	4
Nausea	2/16 (12.5%)	2
Vomiting	1/16 (6.3%)	1
General disorders
Edema	1/16 (6.3%)	1
Fatigue	4/16 (25%)	5
Hemorrhage	1/16 (6.3%)	1
Pain	2/16 (12.5%)	2
Infections and infestations
Infection	1/16 (6.3%)	1
Febrile Neutropenia	4/16 (25%)	4
Metabolism and nutrition disorders
Hypercalcemia	1/16 (6.3%)	1
Hyperglycemia	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/16 (6.3%)	1
Nervous system disorders
Dizziness	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)	1
Dyspena	2/16 (12.5%)	2
Skin and subcutaneous tissue disorders
Rash	1/16 (6.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.