Sorafenib and 5-Azacitidine in Acute Leukemia + Myelodysplastic Syndrome

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Bayer
Onyx Therapeutics, Inc.
Celgene Corporation
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01254890
First received: December 3, 2010
Last updated: March 21, 2014
Last verified: March 2014
  Purpose

The goal of this clinical research study is to learn if 5-azacitidine and sorafenib can control the disease in patients with AML or MDS. The safety of this drug combination will also be studied.


Condition Intervention Phase
Leukemia
Drug: Azacitidine
Drug: Sorafenib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Sorafenib and 5-Azacitidine for the Treatment of Patients With Refractory or Relapsed Acute Leukemia and Myelodysplastic Syndrome (MDS) - (VZ-MDS-PI-0227)

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Phase I: Maximum Tolerated Dose (MTD) of AZA + Sorafenib [ Time Frame: Every 28 day cycle ] [ Designated as safety issue: Yes ]
    MTD is defined as highest dose level in which 6 patients treated with at most 1 experiencing a dose limiting toxicity (DLT) during 1st cycle. One cycle of therapy is 7 days of azacitidine (AZA) and 28 days of sorafenib.


Secondary Outcome Measures:
  • Phase II: Overall Response (CR+CRi) after 3 Cycles [ Time Frame: 90 days ] [ Designated as safety issue: No ]
    Overall response (CR+CRi) after three cycles of treatment where CR is Complete Response and CRi is Complete remission with incomplete blood count recovery according to International Working Group response criteria for AML (JCO 2003; 21: 4642-9).


Estimated Enrollment: 60
Study Start Date: January 2011
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azacitidine + Sorafenib
Azacitidine (AZA) 75 mg/m2 SQ or IV daily x 7; Sorafenib 200 mg orally twice a day.
Drug: Azacitidine
75 mg/m2 subcutaneously (SQ) or by vein (IV) daily for 7 days per 28 day cycle.
Other Names:
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
Drug: Sorafenib
Starting dose level 200 mg by mouth two times a day in a 28 day cycle. In Phase II, Sorafenib administered per MTD dose from Phase I. Drug doses separated by approximately 12 hours.
Other Names:
  • Nexavar
  • BAY43-9006

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with MDS, CMML or AML, who have failed pror therapy (including low and intermediate risk patient who have required prior therapy).
  2. Patients with MDS or CMML should have failed prior therapy with a hypomethylating agent and/or with lenalidomide. Patients who have received prior azacitidine are eligible if the treating physician feels that participation in the sudy is in the patients' best interest.
  3. Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy.
  4. Patients with MDS or CMML who received therapy with hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless of any prior therapy for AML.
  5. Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive or refuse standard therapy.
  6. Age of greater than or equal to 18 years of age.
  7. ECOG Performance Status less than or equal to 2.
  8. Adequate liver (bilirubin less than or equal 1.5 x ULN, ALT and AST less than or equal 2.5 x ULN and Alkaline phosphatase less than 4 x ULN if not related to leukemic disease) and renal (creatinine less than or equal 1.5x ULN) function. Amylase and Lipase must be less than or equal 2 X ULN.
  9. Patients must provide written informed consent.
  10. Patients must have been off chemotherapy for 2 weeks prior to entering this study, unless there is evidence of rapidly progressive disease, and must have recovered from the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy but should be stopped for 24 hours prior to initiation of azacitidine.
  11. 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 azacytidine. 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 a year) and surgically sterilized women are not required to undergo a pregnancy test.
  12. Females of childbearing potential Recommendation is for 2 effective contraceptive methods during the study. 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.
  13. 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.
  14. 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.
  15. INR less than 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 at least 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 unless multiply refractory and no other standard treatment strategies are available to them
  3. Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.
  4. Patients with known 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 poorly controlled 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 of Day 1.
  8. Patients unwilling or unable to comply with the protocol.
  9. Patients with known malignant disease of the central nervous system or advanced malignant hepatic tumors.
  10. Cardiac disease: Congestive heart failure greater than class II 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.
  11. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  12. Uncontrolled hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg, despite optimal medical management.
  13. Active clinically serious infection greater than CTCAE v4. Grade 2 not controlled with antibiotics.
  14. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
  15. Pulmonary hemorrhage/bleeding event greater than CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.
  16. Any other hemorrhage/bleeding event greater than CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.
  17. Serious non-healing wound, ulcer, or bone fracture.
  18. Evidence or history of bleeding diathesis or coagulopathy
  19. Known or suspected allergy to sorafenib or any agent given in the course of this trial.
  20. Patients with a history of solid organ transplant
  21. Patients with seizure disorder requiring medication (such as antiepileptics).
  22. Use of strong CYP3A4 inducers (eg, St. John's wort, dexamethasone at a dose of greater than 16 mg daily, phenytoin, carbamazepine, rifabutin, phenobarbital, or rifampin within seven days of initiating dosing
  23. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01254890

Locations
United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bayer
Onyx Therapeutics, Inc.
Celgene Corporation
Investigators
Principal Investigator: Farhad Ravandi-Kashani, MD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided by M.D. Anderson Cancer Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01254890     History of Changes
Other Study ID Numbers: 2010-0511, NCI-2011-00257
Study First Received: December 3, 2010
Last Updated: March 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Relapsed Acute Leukemia
Chronic Myelomonocytic Leukemia
CMML
Myelodysplastic Syndrome
MDS
Acute myeloid leukemia
AML
5-azacitidine
Azacitidine
5-aza
Vidaza
5-AZC
AZA-CR
Ladakamycin
NSC-102816
Sorafenib
Nexavar
BAY43-9006

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Sorafenib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014