Open Label, Phase II Dosing Study of Ara-C Chemotherapy in Combination With EL625 and Idarubicin in Refractory and Relapsed Acute Myelogenous Leukemia (AML)
This clinical trial is designed to assess the ability of cenersen sodium (EL625) in
combination with Idarubicin alone or with Cytarabine to either: (1) induce remissions in
patients who have previously failed to go into remission in response to chemotherapy; or (2)
provide patents who have relapsed after going into a chemotherapy-induced remission with a
Cenersen sodium is one of a new class of drugs called antisense oligonucleotides (oligos).
Oligos are designed to block the production of specific proteins and thereby inhibit their
function. Cenersen sodium targets p53, a widely studied protein.
In cancer, p53 occurs either in the un-mutated ("normal") or mutated forms. The majority of
participants in this trial are expected to have un-mutated p53. Cenersen sodium is
anticipated to sensitize cancers with un-mutated p53 to most established cancer
p53 has a pivotal role in protecting the body from cells that have suffered genetic damage
and, as a result, do not function properly. The protein first senses the level of the damage
and then forces the damaged cell to respond to the damage either by repairing itself or
committing suicide. In general, the greater the level of damage the more likely the cellular
response will be suicide.
Many cancer therapeutics, including both chemotherapy and radiation, cause the types of
genetic damage that activate p53 and, consequently, cause either damage repair or cellular
suicide. Laboratory studies suggest that cancer cells have a host of defenses that reduce
the chances that these cells will respond to genetic damage by committing suicide. So
compared to normal cells, cancer cells are more likely to repair the damage caused by cancer
therapeutics while normal cells are more likely to commit suicide. Thus, blocking un-mutated
p53 is more likely to prevent repair in cancer cells while preventing suicide in normal
cells. This provides the basis for a differential effect of cenersen sodium on cancer cells
verses normal cells.
When p53-dependent repair is prevented in cancer cells they begin to copy their damaged
genetic information in preparation for cell division. This copying of the genetic damage
triggers a p53-independent backup suicide mechanism and, as a result, the cancer cells are
eliminated. This is the presumed mechanism whereby cenersen sodium is able to sensitize
cancer cells with normal p53 function to numerous cancer therapeutics.
At higher doses however, chemotherapy sometimes blocks cells from copying their genes in
preparation for division. Thus, it is possible that a chemotherapeutic agent used at a high
dose could block any sensitizing effect that cenersen sodium might otherwise have on the
The chemotherapeutic agent Idarubicin is known to produce the type of genetic damage that
effects p53 expression, causes p53-dependent responses and has been shown to be made more
effective at killing cancer cells by cenersen sodium. Cytarabine (Ara-C) is the most widely
used chemotherapeutic agent for AML. Cenersen sodium does not appear to sensitize cancer
cells to Cytarabine and at higher doses Cytarabine may reduce the capacity of cenersen
sodium to sensitize cancer cells.
Hence, this AML study will examine the effects of Cenersen sodium used in combination with
Idarubicin and one of three different doses of Cytarabine (i.e. 0, 0.1 and 1.0 gm/m2/day),
on the responsiveness of participants to these chemotherapeutic agents.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the effective dose of Cytarabine chemotherapy to be used in combination with EL625 and Idarubicin.
Jorge E Cortes, MD
M.D. Anderson Cancer Center
United States: Food and Drug Administration
|Roswell Park Cancer Institute||Buffalo, New York 14263|
|North Shore University Hospital||Manhasset, New York 11030|
|M. D. Anderson Cancer Center||Houston, Texas 77030|
|University of California, San Diego||La Jolla, California 92037-1709|
|University of Miami Health Center||Miami, Florida 33136|
|Washington University Medical Center (Siteman Cancer Center)||St. Louis, Missouri 63110|