NCT01039363 (Clinical Trial / Gemtuzumab Ozogamicin)

Study Title
Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia (NCT01039363)

Trial Description
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 I study determined the maximum tolerated dose (MTD) of oral Vorinostat as 200 mg twice daily or 250 mg thrice daily. In addition, the phase I 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 the antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), which is a calicheamicin-conjugated antibody directed against CD33 antigen on AML blasts. The U.S. Food and Drug Administration (FDA) also approved the use of gemtuzumab ozogamicin in 2000 for the treatment of relapsed AML as a monotherapy.

A study also showed that the combinational therapy of gemtuzumab ozogamicin with attenuated doses of standard induction chemotherapy could successfully induce complete response (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 gemtuzumab ozogamicin toward CD33+ AML cells. The study demonstrated that the strategy using HDAC inhibitor together with gemtuzumab ozogamicin 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 gemtuzumab ozogamicin (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 the treatment related mortality (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.

This trial is sponsored by Samsung Medical Center. [1]

Study Data

Study Schematic

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Last Editorial review: July 21, 2015
Information based on ClinicalTrials.gov (NIH/NCI) and other sources.

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