Clinical trial NCT00818649: Bortezomib and Vorinostat in Treating Patients With High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia
Official title: Phase II Trial of Velcade Plus Vorinostat in the Treatment of High Risk MDS and Relapsed/Refractory AML
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia
Myelodysplastic Syndrome
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)
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: Millennium Pharmaceuticals, Inc.
First posted: 2009-01-08
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Number of Patients by Best Clinical Response
timeFrame: At Completion of Course 3 (Day 63)
Secondary outcomes:
measure: Correlative Laboratory Studies
timeFrame: Pre-Study and After 3 Cycles
measure: Correlation of Cell Alterations With Clinical Response
timeFrame: Pre-Study and After 3 Cycles
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Erica Warlick, MD
role: PRINCIPAL_INVESTIGATOR
References: