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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2009 by Samsung Medical Center.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
Samsung Medical Center
ClinicalTrials.gov Identifier:
NCT01039363
First received: December 23, 2009
Last updated: December 24, 2009
Last verified: October 2009
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: Salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Samsung Medical Center:

Primary Outcome Measures:
  • Progression-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • response rate [ Designated as safety issue: Yes ]

Estimated Enrollment: 27
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01039363

Contacts
Contact: Dong Hwan Kim, M.D.,Ph.D. +82-2-3410-1768 dr.dennis.kim@samsung.com

Locations
Korea, Republic of
Samsung Medical Center Not yet recruiting
Seoul, Korea, Republic of, 135-710
Principal Investigator: Dong Hwan Won, M.D.,Ph.D.         
Sponsors and Collaborators
Samsung Medical Center
Investigators
Principal Investigator: Dong Hwan Kim, M.D.,Ph.D. Division of Hematology and Oncology/Samsung Medical Center
  More Information

Publications:

Responsible Party: Dong Hwan (Dennis) Kim/Assistant professor, Samsung Medical Center
ClinicalTrials.gov Identifier: NCT01039363     History of Changes
Other Study ID Numbers: 2009-08-029
Study First Received: December 23, 2009
Last Updated: December 24, 2009
Health Authority: South Korea: Institutional Review Board

Keywords provided by Samsung Medical Center:
Relapse or refractory acute myeloid leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Vorinostat
Gemtuzumab
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on September 22, 2014