Bortezomib and Vorinostat in Treating Patients With High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia
Condition: Leukemia; Myelodysplastic Syndrome
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: bortezomib; vorinostat
Intervention description: 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle; 400 mg orally (po) every day on days 1-14 of a 21 day cycle
Intervention MeSH terms: Bortezomib; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; refractory anemia with excess blasts; adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute minimally differentiated myeloid leukemia (M0); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b); adult acute megakaryoblastic leukemia (M7); recurrent adult acute myeloid leukemia; untreated adult acute myeloid leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22)

Summary:

      RATIONALE: Bortezomib and vorinostat may stop the growth of cancer cells by blocking some of
      the enzymes needed for cell growth. Giving bortezomib together with vorinostat may kill more
      cancer cells.

      PURPOSE: This phase II trial is studying how well giving bortezomib together with vorinostat
      works in treating patients with high-risk myelodysplastic syndrome or acute myelogenous
      leukemia.
    

Eligibility criteria:

        Inclusion Criteria:

        Disease Specific Criteria: Pathologic Diagnosis must be confirmed by University of
        Minnesota Hematopathology

          -  Myelodysplastic Syndrome (MDS): By IPSS Category: INT-2 or High risk, By WHO
             Classification: RAEB-1 or RAEB-2,By cytogenetics: High Risk Cytogenetic Abnormality
             Present as defined by the presence Monosomy 7 or complex karyotype. Patients will be
             eligible after progressing through standard therapy with either Azacitidine or
             Decitabine. Patients with a history of 5q minus syndrome may be eligible after
             progressing through treatment with Lenalidomide.

          -  Acute Myelogenous Leukemia (AML): Histologic subtypes M0,M1,M2,M4,M5,M6,M7 are
             eligible and must meet one of the three criteria below:

               -  Refractory Disease/Induction Failure: Failure to achieve initial remission after
                  2 lines of induction therapy.

               -  Relapsed Disease

               -  Newly diagnosed/untreated AML: Patients who are not able to tolerate potentially
                  curative conventional induction chemotherapy due to advanced age, end organ
                  limitations, or performance status limitation will be eligible.

        Additionally, those that refuse conventional induction therapy will be eligible.

          -  Patients must have relatively stable bone marrow function during the week prior to
             enrollment on the study. White Blood cells (WBC) may be controlled with hydrea. Rapid
             WBC doubling not responsive to control with hydrea would indicate unstable bone marrow
             function. Ideally WBC should be < 15 X 10^3 /dl at time of study enrollment.

          -  Age >18 years

          -  Karnofsky performance status > or = 60%

          -  Have acceptable organ function as defined within 28 days of enrollment:

               -  Hematologic: hemoglobin > 8 g/dL, and platelets > 20k. (Patients may receive
                  transfusions of either peripheral red blood cells (PRBC) or platelets to achieve
                  these levels)

               -  Renal: creatinine < or = 2.0 mg/dL or creatinine clearance > or = 40 ml/min

               -  Hepatic: ALT, AST < or = 2.5 x upper limit of normal and total bilirubin < or =
                  1.5 X ULN

               -  Cardiac: left ventricular ejection fraction > 40% (testing required for all
                  patients. For those with prior cardiac history (defined as prior stent or bypass
                  surgery) a stress test within 1 month prior to proceeding with the study will be
                  required. A cardiology consult will be required for those with prior documented
                  cardiac disease or those with any significant EKG/ECHO abnormalities found on
                  screening tests.

          -  Patients must not have received treatment for their myeloid disorder within 2 weeks of
             beginning the trial. Treatments include the use of chemotherapy, hematopoietic growth
             factors, and biologic therapy such as monoclonal antibodies. The exception is the use
             of hydroxyurea for patients with an elevated WBC. Given the relatively slower expected
             clinical response with the study drugs, patients may continue to receive hydroxyurea
             through the first cycle of therapy.

          -  Must have recovered from clinically significant toxicities from previous therapies.

          -  Women of child bearing potential must agree to use adequate contraception (diaphragm,
             birth control pills, injections, intrauterine device [IUD], surgical sterilization,
             subcutaneous implants, or abstinence, etc.) for the duration of treatment. In
             addition, women of childbearing potential must have a negative serum pregnancy test
             b-hCG within 72 hours prior to receiving the first dose of therapy. Sexually active
             men must agree to use barrier contraceptive for the duration of treatment.

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care.

          -  Treatment History Criteria: Patients who have relapsed after allogeneic stem cell
             transplantation are eligible.

        Exclusion Criteria:

          -  Pregnant or lactating. The agents used in this study are known to be teratogenic to a
             fetus and there is no information on the excretion of agents into breast milk. All
             females of childbearing potential must have a blood test within 72 hours prior to
             study drug administration to rule out pregnancy.

          -  Grade 2 or greater peripheral neuropathy within 14 days before enrollment

          -  Active central nervous system (CNS) disease. Patients with any clinical symptoms of
             active CNS disease must have LP with negative cytology.

          -  WBC and Peripheral Blast count uncontrolled with hydroxyurea

          -  Evidence of QT prolongation with QTc interval greater than 0.5 seconds. QTc
             calculation from the EKG machine will be used for this assessment.

          -  Clinical evidence of heart failure or history of uncontrolled hypertension. Myocardial
             infarction within 6 months prior to enrollment or has New York Heart Association
             (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled
             ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
             conduction system abnormalities. Prior to study entry, any ECG abnormality at
             Screening has to be documented by the investigator as not medically relevant.

          -  Patients with untreated positive blood cultures or progressive infections as assessed
             by radiographic studies

          -  Patients with prior use of other histone deacetylase inhibitors (excluding valproic
             acid for seizures with a 30 day wash-out period)

          -  Known hypersensitivity to Velcade, boron or any of the other agents used in this study

          -  Patients with a history of deep vein thrombosis/pulmonary embolism (DVT/PE) that has
             not been adequately treated with systemic anticoagulation or that has been recently
             diagnosed (within the last 2 months).

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

          -  Active HIV or viral hepatitis infection

          -  Other active and potentially life threatening malignancies excluding localized basal
             cell or squamous cell skin cancers, cervical carcinoma in situ, superficial bladder
             cancer, localized prostate cancer.