Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia

December 24, 2009 updated by: Samsung Medical Center

Phase II Clinical Evaluation of Vorinostat Combined With Salvage Reinduction Chemotherapy Including Gemtuzumab Ozogamicin, Idarubicin and Cytarabine and Vorinostat Maintenance in Relapse or Refractory Acute Myeloid Leukemia Patients With 50 Years or Older

The prognosis of elderly patients with relapsed or refractory acute myeloid leukemia (AML) is grave. Because of their chronological age and/or the presence of multiple co-morbidities, treatment-related mortality in elderly patients with AML is quite high although higher intensive treatment is mandatory to overcome chemoresistant characteristic of their disease. Several regimens have been evaluated as salvage chemotherapy for relapsed or refractory AML such as Mitoxantrone/High dose Cytarabine or Amsacrine/High dose Cytarabine. These regimens could achieve complete remission (CR) in a part of patients, but resulted in higher treatment related mortality (TRM). Accordingly, less intensive salvage regimen is needed for elderly patients with relapsed or refractory AML.

The activity of histone deacetylase (HDAC) inhibitor, Vorinostat or Suberoylanilide hydroxamic acid (SAHA), against AML has been suggested in cell line models and in animal model as well as in a phase 1 trial. The phase 1 study determined the MTD of oral Vorinostat as 200mg twice daily or 250mg thrice daily. In addition, the phase 1 trial showed the antitumor activity of Vorinostat with 17% of response rate in patients with advanced leukemia or myelodysplastic syndrome (MDS). Accordingly, further study is recommended to demonstrate the clinical activity of Vorinostat in AML.

In terms of the combining drug with Vorinostat, anthracycline is one of the best candidate. A in vitro study demonstrated that the combination of anthracycline (esp. idarubicin) with HDAC inhibitor have significant clinical activity against leukemia. Another candidate is Gemtuzumab ozogamicin, which is a calicheamicin-conjugated antibody directed against CD33 antigen on AML blasts. The U.S. FDA also approved the use of GO in relapsed AML as a monotherapy. A study also showed that the combinational therapy of GO with attenuated doses of standard induction chemotherapy could successfully induce CR without increasing treatment-related mortality in AML patients aged 55 or older. A in vitro study reported that HDAC inhibitor valproic acid augmented the clinical activity of GO toward CD33+ AML cells. The study demonstrated that the strategy using HDAC inhibitor together with GO could potentially induce synergistic proapoptotic activity against AML blasts without increasing toxicity. In our center, so far we treated relapsed or refractory AML patients using the salvage regimen including GO (3mg/m2/dayx1day) plus attenuated Idarubicin/Cytarabine (Idarubicin 12mg/m2/day for 2 days and intermediate dose Cytarabine). So far, the CR rate from the regimen is around 50% without increasing TRM. Accordingly, we will determine the efficacy and toxicity of Vorinostat-incorporating salvage regimen based on the GO+IA chemotherapy in patients 50 years old or older with relapsed or refractory AML.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

27

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age > 50 years.
  2. ECOG Performance Status of 0, 1 or 2
  3. Life expectancy of at least 12 weeks.
  4. Subjects in relapse or refractory after any kinds of chemotherapy for acute myeloid leukemia expressing CD33 antigen on ≥ 50% of myeloblasts.

  5. Adequate liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days and adequate bone marrow within 14 days prior to screening:

    1. Total bilirubin < 1.5 times the upper limit of normal
    2. ALT and AST < 2.5 x upper limit of normal
    3. Alkaline phosphatase < 4 x ULN
  6. PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.]
  7. Serum creatinine < 1.5 x upper limit of normal.
  8. Signed and dated informed consent before the start of specific protocol procedures.

Exclusion Criteria:

  1. History of cardiac disease: congestive heart failure >NYHA class 3 or 4; active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension.
  2. History of HIV infection or chronic hepatitis B or C (except the case receiving Lamivudine or entecavir and in control of HBV infection)
  3. Active clinically serious infections (> grade 2 NCI-CTC version 3.0)
  4. Patients with seizure disorder requiring medication (such as anti-epileptics)
  5. Patients with evidence or history of bleeding diasthesis before diagnosis of acute myeloid leukemia
  6. Patients undergoing renal dialysis
  7. Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry.
  8. Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed). Major surgery within 4 weeks of start of study
  9. Investigational drug therapy outside of this trial during or within 4 weeks of study entry
  10. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  11. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study, such as Alzheimer's disease or dementia
  12. Patients unable to swallow oral medications.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Vorinostat
Vorinostat combined with salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat maintenance
Drug: Salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat

Salvage reinduction therapy:

Vorinostat 200mg BID po (D1-14) Gemtuzumab ozogamicin 3 mg/m2 once (D1) Idarubicin 12mg/m2 for 2 days (D2-3) Cytarabine 500mg/m2 bid IV for 5 days (D2-6)

Maintenance:

Once achieved CR, then Vorinostat 200mg BID po for 2 weeks, then 1 week's rest (1 cycle) for 11 cycles

  • Vorinostat should be stopped at least 2 weeks ahead of starting of consolidation therapy.
  • Gemtuzumab will be omitted in a consolidation schedule.
  • Allogeneic hematopoietic stem cell transplantation (HSCT) can be performed if HLA-matched sibling or unrelated donor is available. Vorinostat will be stopped 2 weeks prior to starting of conditioning regimen for allogeneic HSCT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Progression-free survival

Secondary Outcome Measures

Outcome Measure
response rate

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Samsung Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

First Submitted

December 23, 2009

First Submitted That Met QC Criteria

December 24, 2009

First Posted (Estimate)

December 25, 2009

Study Record Updates

Last Update Posted (Estimate)

December 25, 2009

Last Update Submitted That Met QC Criteria

December 24, 2009

Last Verified

October 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2009-08-029

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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