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Open Label, Phase II Dosing Study of Ara-C Chemotherapy in Combination With EL625 and Idarubicin in Refractory and Relapsed Acute Myelogenous Leukemia (AML)

Phase 2
18 Years
Not Enrolling
Acute Myelogenous Leukemia

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Trial Information

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
longer remission.

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.

Inclusion Criteria

Inclusion Criteria

- Subjects with either refractory AML (not achieving a CR after a single course of
induction), or relapsed AML that have a CR for less than one year.

- greater or equal to 18 years old.

- Life expectancy of more than 4 weeks following initiation of treatment.

- Performance status (Zubrod) less or equal to 3.

- Total Bilirubin less or equal to 1.5 x upper normal limit (UNL) unless attributable
to organ infiltration by leukemia, and ALT(SGPT) less or equal to 2.5 x UNL.

- Creatinine less or equal to 1.5 x UNL unless attributable to organ infiltration by

- If plasma creatinine value is borderline, creatinine clearance greater or equal to 60
ml/min (actual or calculated), serum magnesium should be within the normal value.

- Subjects with liver and/or renal dysfunction due to organ infiltration by leukemia
are eligible.

- Left Ventricular Ejection Volume (LVEF) of >50% as determined by multi-gated
acquisition scan (MUGA) or echocardiogram.

- Able to comply with scheduled follow-up and with management of toxicity.

- Sexually active patients must use an effective method of contraception during the
study dosing period. The following are considered acceptable methods of
contraception: (i) oral contraceptive pill, (ii) condom, (iii) diaphragm plus
spermicide, (iv) patient or partner surgically sterile, (v) patient or partner more
than 2 years post-menopausal or (vi) injectable or implantable agent/device.

- Informed consent form obtained, signed and dated prior to initiation of treatment

Exclusion Criteria:

- Subjects with M3 AML.

- Subjects receiving other anti-leukemia investigational agents (i.e., unapproved
drugs). However, individual cases will be considered on a case-by-case basis for
other investigational agents (e.g., antibiotics, antifungals).

- Pregnant or lactating subjects. Chemotherapy (including hydroxyurea) within three (3)
weeks prior to initiation of therapy, unless there is evidence of rapidly progressive
disease; then subjects may be enrolled with a minimum of two (2) weeks from previous

Prohibited Medications during the first week of each course:

- Acetaminophen

- Hi-Dose antioxidants (e.g., Vitamins C, E; Multivitamins)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the effective dose of Cytarabine chemotherapy to be used in combination with EL625 and Idarubicin.

Principal Investigator

Jorge E Cortes, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2004

Completion Date:

May 2007

Related Keywords:

  • Acute Myelogenous Leukemia
  • Refractory or Relapsed Acute Myelogenous Leukemia (AML)
  • Antisense
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



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