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LeukemiaPhase 1/2NCT01254890

Sorafenib and 5-Azacitidine in Acute Leukemia + Myelodysplastic Syndrome

A Phase 1/2 study testing Azacitidine and Sorafenib in people with Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia
What is being tested?
Azacitidine and Sorafenib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
1 siteUnited States
Study dates
Jan 2011to Mar 2015
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with MDS, CMML or AML, who have failed pror therapy (including low and intermediate risk patient who have required prior therapy).
  • 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.
  • Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy.
  • 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.
  • Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive or refuse standard therapy.
  • Age of greater than or equal to 18 years of age.
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  • ECOG Performance Status less than or equal to 2.
  • Adequate liver (bilirubin less than or equal 1.5 * upper limit of normal (ULN), ALT and AST less than or equal 2.5 * ULN and Alkaline phosphatase less than 4 * ULN if not related to leukemic disease) and renal (creatinine less than or equal 1.5* ULN) function. Amylase and Lipase must be less than or equal 2 * ULN.
  • Patients must provide written informed consent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Who cannot join

  • Nursing and pregnant females.
  • Patients with acute promyelocytic leukemia are excluded unless multiply refractory and no other standard treatment strategies are available to them
  • Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.
  • Patients with known 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 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.
  • Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis (B or C).
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  • Patients who have had any major surgical procedure within 28 days of Day 1.
  • Patients unwilling or unable to comply with the protocol.
  • Patients with known malignant disease of the central nervous system or advanced malignant hepatic tumors.
  • 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.
  • Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  • Uncontrolled hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg, despite optimal medical management.
  • Active clinically serious infection greater than 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 greater than CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.
  • Any other hemorrhage/bleeding event greater than CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.
  • Serious non-healing wound, ulcer, or bone fracture.
  • Evidence or history of bleeding diathesis or coagulopathy
  • Known or suspected allergy to sorafenib or any agent given in the course of this trial.
  • Patients with a history of solid organ transplant
  • Patients with seizure disorder requiring medication (such as antiepileptics).
  • 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
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

Trial locations and contacts

1 site in 1 country.

United States1 site

  • UT MD Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

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)

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.

Read the detailed description

The Study Drugs:

Sorafenib is designed to block the function of important proteins in cancer cells. These proteins, when active, are partly responsible for the abnormal growth and behavior of cancer cells.

5-Azacytidine is designed to activate ("turn on") certain genes in cancer cells whose job is to fight tumors.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive 5-azacytidine either 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 water on empty stomach, every day.

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

Study Visits:

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

Every 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:

  • Your performance status will be recorded.
  • You will have a physical exam, including measurement of your blood pressure and weight.

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 the 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.

Your participation on the study will be over once you have completed the end-of-treatment and follow-up visits.

End of Study Drug Administration Visit:

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

  • Your medical history will be recorded.
  • Your performance status will be recorded.
  • You will have a physical exam, including measurement of your blood pressure and weight.
  • You will have a bone marrow aspirate collected to check the status of disease.

This is an investigational study. Sorafenib is FDA approved and commercially available for kidney cancer and liver cancer. 5-Azacitidine is FDA approved for the treatment of MDS, but its combination with sorafenib is investigational.

Up to 60 patients will take part in this study. All will be enrolled at MD Anderson.

Conditions
Leukemia
Being tested
Azacitidine, Sorafenib
Keywords
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
Medical subject headings
Leukemia, Leukemia, Myelomonocytic, Chronic, Myelodysplastic Syndromes, Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AzacitidineDrug

    Also called 5-aza, Vidaza, 5-AZC, AZA-CR

    75 mg/m^2 subcutaneously (SQ) or by vein (IV) daily for 7 days per 28 day cycle.

  • SorafenibDrug

    Also called Nexavar, BAY43-9006

    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.

Study groups in NCT01254890
Study groupRoleWhat they receive
Azacitidine + SorafenibExperimentalAzacitidine (AZA) 75 mg/m^2 subcutaneously (SQ) or intravenously (IV) daily for 7 days; Sorafenib 200 mg orally twice a day.
Receives: Drug: Azacitidine; Drug: Sorafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase I: Maximum Tolerated Dose (MTD) of Sorafenib Given With Azacitidine

    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. Starting dose of Sorafenib is 200 mg twice a day azacitidine

    Measured: 28 day cycle

Secondary outcomes (1)

  1. Phase II: Number of Participants With Response

    Response according to International Working Group response criteria for Acute myeloid leukemia (AML) (JCO 2003; 21: 4642-9): CR defined by presence of <5% blasts in the bone marrow (BM), with >1 X 10^9/L neutrophils and >100 x 10^9/L platelets in the peripheral blood (PB) with no detectable extramedullary disease. Participants who met the above criteria but had neutrophil or platelet counts less than the stated values were considered to have achieved CRi (CR with incomplete recovery of PB counts) or CR with incomplete platelet recovery (CRp) if CR but platelets < 100 x 10^9/L but ≥ 50 x 10^9/L and platelet transfusion independent. Partial response (PR) required all of the hematologic values for a CR but with a decrease of >/= 50% in the percentage of blasts to 5% to 25% in the BM aspirate.

    Measured: 90 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Dec 2010 (estimated)
  2. Study startJan 2011
  3. Primary completionMar 2015
  4. Study completionMar 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01254890
Sponsor's protocol ID
2010-0511
Other IDs
NCI-2011-00257
Status last verified
Mar 2016
First submitted
3 Dec 2010
Last updated
6 May 2016
Data monitoring committee
No

Publications

  • 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.

    PubMed 30028037

  • Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. doi: 10.1182/blood-2013-01-480228. Epub 2013 Apr 23.

    PubMed 23613521

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Azacitidine and Sorafenib in people with Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 May 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 May 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Maximum Tolerated Dose (MTD) of Sorafenib Given With Azacitidine (time frame: 28 day cycle). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01254890, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 May 2016.

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