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Trial Title:
Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia
NCT ID:
NCT01039363
Condition:
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Cytarabine
Vorinostat
Idarubicin
Gemtuzumab
Conditions: Keywords:
Relapse or refractory acute myeloid leukemia
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Unknown status
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat
Description:
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.
Arm group label:
Vorinostat
Summary:
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.
Criteria for eligibility:
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.
Gender:
All
Minimum age:
50 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Samsung Medical Center
Address:
City:
Seoul
Zip:
135-710
Country:
Korea, Republic of
Investigator:
Last name:
Dong Hwan Won, M.D.,Ph.D.
Email:
Principal Investigator
Lead sponsor:
Agency:
Samsung Medical Center
Agency class:
Other
Source:
Samsung Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01039363