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Phase II Trial of Velcade Plus Vorinostat in the Treatment of High Risk MDS and Relapsed/Refractory AML

Phase 2
18 Years
Not Enrolling
Leukemia, Myelodysplastic Syndrome

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Trial Information

Phase II Trial of Velcade Plus Vorinostat in the Treatment of High Risk MDS and Relapsed/Refractory AML



- To determine the clinical response to bortezomib and vorinostat in patients with
high-risk myelodysplastic syndromes or acute myeloid leukemia, as defined by the
International Working Group response criteria.


- To characterize the quantitative and qualitative toxicities of this regimen in these

- To assess the effect of this regimen on natural killer (NK) cell function, in terms of
activating and inhibitory receptor alterations, target cell ligand and HLA class I
modulation, and NK-mediated cell killing.

- To correlate the above changes with clinical response.

OUTLINE: Patients receive bortezomib subcutaneously (SQ) on days 1, 4, 8, and 11 and oral
vorinostat once daily on days 1-14. Treatment repeats every 21 days for 3 courses in the
absence of disease progression or unacceptable toxicity. Patients who achieve a complete
response, partial response, or hematologic improvement may receive 3 additional courses of
therapy (for a maximum of 6 courses).

Bone marrow and peripheral blood samples are collected at baseline and at the completion of
3 courses of therapy for analysis of target cells (myeloid blasts) (i.e., HLA class I
receptor analysis and natural killer [NK] cell receptor ligand analysis) and analysis of
activating NK cell receptor alterations and NK-mediated cell killing.

After completion of study treatment, patients are followed periodically for up to 1 year.

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

- 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients by Best Clinical Response

Outcome Description:

Assessed by the International Working Group response criteria: Categories include Complete Remission (CR), Partial Remission (PR), Marrow CR, Hematologic Improvement (HI), Stable Disease, Cytogenic Response and Disease Progression. clinical response = CR+PR+HI. Thus, all patients who complete at least 1 full cycle of therapy will be considered evaluable for response.

Outcome Time Frame:

At Completion of Course 3 (Day 63)

Safety Issue:


Principal Investigator

Erica Warlick, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

May 2012

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndrome
  • 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)
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



Masonic Cancer Center, University of Minnesota Minneapolis, Minnesota  55455