Bortezomib and Vorinostat in Treating Patients With High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

Sponsor
Masonic Cancer Center, University of Minnesota (Other)
Overall Status
Terminated
CT.gov ID
NCT00818649
Collaborator
Merck Sharp & Dohme LLC (Industry), Millennium Pharmaceuticals, Inc. (Industry)
16
1
1
40
0.4

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

OBJECTIVES:

Primary

  • 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.

Secondary

  • To characterize the quantitative and qualitative toxicities of this regimen in these patients.

  • 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
16 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Trial of Velcade Plus Vorinostat in the Treatment of High Risk MDS and Relapsed/Refractory AML
Study Start Date :
Jan 1, 2009
Actual Primary Completion Date :
May 1, 2012
Actual Study Completion Date :
May 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Velcade + Vorinostat

This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles.

Drug: bortezomib
1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
Other Names:
  • Velcade
  • Drug: vorinostat
    400 mg orally (po) every day on days 1-14 of a 21 day cycle
    Other Names:
  • suberoylanilide hydroxamic acid (SAHA)
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Patients by Best Clinical Response [At Completion of Course 3 (Day 63)]

      Assessed by the International Working Group response criteria: Complete Remission - <5% myeloblasts with normal maturation of all cell lines; Partial Remission - bone marrow blasts decreased by > 50% over pre-treatment but still >5%; and Hematologic Improvement - hemoglobin increase by > 1.5g/dl or decreased transfusions by at least 4/8 week period, platelet absolute increase of >30 X 10^9/L for those starting at >20 X 10^9/L . For those < 20 X 10^9 /L at baseline increase by 100%.

    Secondary Outcome Measures

    1. Correlative Laboratory Studies [Pre-Study and After 3 Cycles]

      Analysis of Natural Killer (NK) Cell Activating and Inhibitory Receptor Alterations, NK Cell Receptor Ligand Alterations, HLA Class I Expression on Target Cells (Myeloid Blasts), and NK-mediated Cell Killing

    2. Correlation of Cell Alterations With Clinical Response [Pre-Study and After 3 Cycles]

      Analysis of Natural Killer (NK) Cell Activating and Inhibitory Receptor Alterations, NK Cell Receptor Ligand Alterations, HLA Class I Expression on Target Cells (Myeloid Blasts), and NK-mediated Cell Killing

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Masonic Cancer Center, University of Minnesota Minneapolis Minnesota United States 55455

    Sponsors and Collaborators

    • Masonic Cancer Center, University of Minnesota
    • Merck Sharp & Dohme LLC
    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Principal Investigator: Erica Warlick, MD, Masonic Cancer Center, University of Minnesota

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT00818649
    Other Study ID Numbers:
    • 2008LS044
    • MT2008-06R
    • 0808M44081
    • MILLENNIUM-X05269
    First Posted:
    Jan 8, 2009
    Last Update Posted:
    Dec 28, 2017
    Last Verified:
    Dec 1, 2017

    Study Results

    Participant Flow

    Recruitment Details Study entry is open to patients regardless of gender or ethnic background.
    Pre-assignment Detail
    Arm/Group Title Velcade + Vorinostat in MDS and AML
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    Period Title: Overall Study
    STARTED 16
    COMPLETED 12
    NOT COMPLETED 4

    Baseline Characteristics

    Arm/Group Title Velcade + Vorinostat
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    Overall Participants 16
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    8
    50%
    >=65 years
    8
    50%
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    65.5
    Sex: Female, Male (Count of Participants)
    Female
    8
    50%
    Male
    8
    50%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    6.3%
    White
    15
    93.8%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    16
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Patients by Best Clinical Response
    Description Assessed by the International Working Group response criteria: Complete Remission - <5% myeloblasts with normal maturation of all cell lines; Partial Remission - bone marrow blasts decreased by > 50% over pre-treatment but still >5%; and Hematologic Improvement - hemoglobin increase by > 1.5g/dl or decreased transfusions by at least 4/8 week period, platelet absolute increase of >30 X 10^9/L for those starting at >20 X 10^9/L . For those < 20 X 10^9 /L at baseline increase by 100%.
    Time Frame At Completion of Course 3 (Day 63)

    Outcome Measure Data

    Analysis Population Description
    Evaluable patients are defined as those who completed at least 1 cycle of therapy; 8 had acute myeloid leukemia, 4 had myelodysplastic syndrome.
    Arm/Group Title Evaluable Patients
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment continued for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    Measure Participants 12
    Complete Remission
    1
    Progressive Disease
    6
    Stable Disease
    5
    2. Secondary Outcome
    Title Correlative Laboratory Studies
    Description Analysis of Natural Killer (NK) Cell Activating and Inhibitory Receptor Alterations, NK Cell Receptor Ligand Alterations, HLA Class I Expression on Target Cells (Myeloid Blasts), and NK-mediated Cell Killing
    Time Frame Pre-Study and After 3 Cycles

    Outcome Measure Data

    Analysis Population Description
    Natural Killer cell studies were discontinued after the first 3 patients because the results were not helpful, and thus the secondary outcome measures were not completed.
    Arm/Group Title Velcade + Vorinostat in MDS and AML
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    Measure Participants 0
    3. Secondary Outcome
    Title Correlation of Cell Alterations With Clinical Response
    Description Analysis of Natural Killer (NK) Cell Activating and Inhibitory Receptor Alterations, NK Cell Receptor Ligand Alterations, HLA Class I Expression on Target Cells (Myeloid Blasts), and NK-mediated Cell Killing
    Time Frame Pre-Study and After 3 Cycles

    Outcome Measure Data

    Analysis Population Description
    Natural Killer cell studies were discontinued after the first 3 patients because the results were not helpful. So, secondary outcome measures were not completed.
    Arm/Group Title Velcade + Vorinostat in MDS and AML
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    Measure Participants 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description All patients treated on the trial were included in evaluation of toxicity. Toxicities are defined as non-hematologic given the concurrent impact of AML and MDS on cytopenias.
    Arm/Group Title Velcade + Vorinostat
    Arm/Group Description This is a phase II two stage single arm study combining Velcade on days 1, 4, 8, and 11 plus oral Vorinostat days 1-14 of a 21 days cycle. Treatment will continue for a total of 3 treatment cycles. vorinostat : 400 mg orally (po) every day on days 1-14 of a 21 day cycle bortezomib : 1.3mg/m^2 via peripheral subcutaneous administration on day 1, 4, 8, 11 of a 21 day cycle
    All Cause Mortality
    Velcade + Vorinostat
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Velcade + Vorinostat
    Affected / at Risk (%) # Events
    Total 3/16 (18.8%)
    Cardiac disorders
    Cardiac arrest 2/16 (12.5%) 2
    Ischemia/Elevated Troponin 1/16 (6.3%) 1
    Other (Not Including Serious) Adverse Events
    Velcade + Vorinostat
    Affected / at Risk (%) # Events
    Total 15/16 (93.8%)
    Blood and lymphatic system disorders
    Febrile neutropenia 1/16 (6.3%) 1
    Cardiac disorders
    Hypotension 2/16 (12.5%) 2
    Ischemia 2/16 (12.5%) 2
    QT prolongation 6/16 (37.5%) 9
    Systolic murmur 2/16 (12.5%) 2
    Eye disorders
    Diplopia 1/16 (6.3%) 1
    Eye pain/blurred vision 2/16 (12.5%) 2
    Gastrointestinal disorders
    Abdominal pain 1/16 (6.3%) 1
    Anorexia 8/16 (50%) 9
    Constipation 5/16 (31.3%) 5
    Dehydration 2/16 (12.5%) 2
    Diarrhea 7/16 (43.8%) 11
    Gingival erythema 1/16 (6.3%) 1
    Mucositis 1/16 (6.3%) 1
    Nausea or vomiting 9/16 (56.3%) 17
    Rectal/hemorrhoidal pain 1/16 (6.3%) 1
    Small bowel obstruction 2/16 (12.5%) 2
    Tongue blister 2/16 (12.5%) 2
    General disorders
    Fatigue 9/16 (56.3%) 10
    Fever 3/16 (18.8%) 6
    Shingles flare 1/16 (6.3%) 1
    Infections and infestations
    Infection, ANC=.03 1/16 (6.3%) 2
    Injury, poisoning and procedural complications
    Hip fracture 1/16 (6.3%) 1
    Investigations
    Elevated ALT/AST/Alkaline Phosphatase 2/16 (12.5%) 10
    Elevated creatinine 4/16 (25%) 10
    Metabolism and nutrition disorders
    Hyperbilirubinemia 1/16 (6.3%) 1
    Hypoalbuminemia 2/16 (12.5%) 2
    Hypoglycemia 1/16 (6.3%) 1
    Hypokalemia 3/16 (18.8%) 6
    Hyponatremia 4/16 (25%) 6
    Musculoskeletal and connective tissue disorders
    Involuntary movements 1/16 (6.3%) 1
    Joint pain 1/16 (6.3%) 1
    Muscle leg pain 1/16 (6.3%) 2
    Muscle weakness 2/16 (12.5%) 2
    Nervous system disorders
    Depression 1/16 (6.3%) 1
    Dizziness 3/16 (18.8%) 5
    Neuropathy 4/16 (25%) 5
    Syncope 2/16 (12.5%) 2
    Psychiatric disorders
    Insomnia 2/16 (12.5%) 2
    Renal and urinary disorders
    Pain upon urination 1/16 (6.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 1/16 (6.3%) 1
    Dyspnea 2/16 (12.5%) 2
    Hypoxia 1/16 (6.3%) 1
    Nose bleeding 1/16 (6.3%) 1
    Pulmonary infection/pneumonia 2/16 (12.5%) 2
    Skin and subcutaneous tissue disorders
    Fash rash 1/16 (6.3%) 1
    Vascular disorders
    Edema 4/16 (25%) 4

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Erica Warlick, M.D.
    Organization Masonic Cancer Center, University of Minnesota
    Phone 612-625-5467
    Email ewarlick@umn.edu
    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT00818649
    Other Study ID Numbers:
    • 2008LS044
    • MT2008-06R
    • 0808M44081
    • MILLENNIUM-X05269
    First Posted:
    Jan 8, 2009
    Last Update Posted:
    Dec 28, 2017
    Last Verified:
    Dec 1, 2017