Phase I/II Study of Combination of Sorafenib, Vorinostat, and Bortezomib for the Treatment of Acute Myeloid Leukemia With Complex- or Poor-risk (Monosomy 5/7) Cytogenetics or FLT3-ITD Positive Genotype

Study Overview
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Brief Summary
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This research is being done because treatment options are very limited and usually unsuccessful for Acute Myeloid Leukemia (AML) in older individuals, or younger people with disease that has relapsed and/or proven resistant to standard therapy. Subjects are invited to participate in this study that will examine the use of three drugs called Sorafenib (Nexavar), Vorinostat (Zolinza) and Bortezomib (Velcade) for treating acute myeloid leukemia.

Official Title
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Phase I/II Study of Combination of Sorafenib, Vorinostat, and Bortezomib for the Treatment of Acute Myeloid Leukemia With Complex- or Poor-risk (Monosomy 5/7) Cytogenetics or FLT3-ITD Positive Genotype

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: sorafenib, vorinostat and bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A confirmed baseline diagnosis of AML by the revised guidelines of the International Working Group for AML including newly diagnosed, relapsed or refractory disease. Poor-risk or complex cytogenetics profile, or deletion of chromosome 5, or deletion of chromosome 7, or positive FLT3-ITD mutation. The patient must have discontinued all previous therapies for acute leukemia for at least 14 days and recovered from the acute non-hematologic side effects of the therapy. Hydroxyurea to control peripheral blood blast count must be discontinued within 24 hours prior to the initiation of treatment. Patients must have an ECOG (Zubrod) performance status of 0-2 Patients must have adequate hepatic and renal function according to the protocol within one week prior to treatment. Female patients must be postmenopausal, surgically sterile or agree to use effective methods of contraception throughout the study. Male patients, even if surgically sterilized, must agree to practice effective contraception throughout the study. Patients must be able to swallow and tolerate oral medications. Exclusion Criteria: Known central nervous system (CNS) leukemia. Diagnosis of acute promyelocytic leukemia (APL). Grade >/= 2 peripheral neuropathy. Serious illness including, significant ongoing or active infection, New York Heart Association (NYHA) Grade III or IV congestive heart failure, unstable angina or new onset angina or myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within past 3 months. Serious medical or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. Active corneal erosions or history of abnormal corneal sensitivity test. Known or suspected history of severe hypersensitivity reaction to tyrosine kinase inhibitors, histone deacetylase inhibitors, proteosome inhibitors, boron, or mannitol. Female patients who are lactating or have a positive serum pregnancy test within 72 hours of initiation of treatment, or a positive urine pregnancy test on Day 1 before first dose of study drug. Concurrent use of other histone deacetylase inhibitors (e.g. valproic acid) are prohibited except for HDAC inhibitors or HDAC-inhibitor like agents used for non-cancer treatment (e.g. epilepsy), where a 14 day washout is allowed. Radiation therapy within 3 weeks before randomization. Patients with known HIV, or known active hepatitis B or C infections.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sorafenib, vorinostat and bortezomib<br>Escalating cohorts of sorafenib, vorinostat and bortezomib | Drug: sorafenib, vorinostat and bortezomib<br>* Escalating dose cohorts of sorafenib, vorinostat and bortezomib. The first cohort will receive sorafenib from day 1 to 14, vorinostat will be given on days 1-4 and 8-12, and bortezomib will be given on days 1 and 8. This will be followed by 7 days of rest. Therefore each cycle will be 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose Limiting Toxicity | The number of patients who had a DLT during the dose finding/confirming portion (Phase I) of the trial for the safety of the combination of sorafenib, vorinostat, and bortezomib. | up to 9 months | 
| Phase II - Percentage of Patients With a Partial Response or Greater | Evaluate the overall response rate of patients receiving therapy. Patients are considered as having a response if their overall response is Partial Response or better. The percentage of patients achieving this and the exact 95% confidence interval will be calculated. Responses will be defined using the response criteria determined by the International Working Group for AML. | up to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Time to Relapse | Will be examined using Kaplan-Meier estimates. Time from date of confirmed complete remission to date of relapse. The observations of patients who died or remained alive and relapse free were censored at date of death or last disease evaluation, respectively. | Up to one year | 
| Phase II - Treatment-Related Adverse Events Grade 3 or Higher | Number of unique patients who had a treatment-related (possible, probable or definite) adverse events that were graded 3 or higher. | Up to one year |