The principal goal of this clinical trial is to assess the ability of EL625 to improve cancer responsiveness to the established AML therapeutic agent Idarubicin used alone or in combination with Cytarabine (Ara-C).

EL625 is a drug that is designed to block the effects of a protein called p53. Laboratory evidence shows that blocking p53 will make many types of cancer, including acute myelogenous leukemia (AML), more sensitive to a variety of established cancer therapeutics while making normal tissues more resistant to the toxic effects of these agents.

Condition	Treatment or Intervention	Phase
Acute Myelogenous Leukemia	Drug: EL625  Drug: Idarubicin  Drug: Ara-C	Phase II

Further Study Details: 

Expected Total Enrollment:  45

This clinical trial is designed to assess the ability of 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.

EL625 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. EL625 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. EL625 is anticipated to sensitize cancers with un-mutated p53 to most established cancer therapeutics.

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 EL625 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 EL625 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 EL625 might otherwise have on the cancer.

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 EL625. Cytarabine (Ara-C) is the most widely used chemotherapeutic agent for AML. EL625 does not appear to sensitize cancer cells to Cytarabine and at higher doses Cytarabine may reduce the capacity of EL625 to sensitize cancer cells.

Hence, this AML study will examine the effects of EL625 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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

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 leukemia.
• 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 treatments.

Douglas Testa, PhD      908 236 9920    dougtesta@patmedia.net
David Kay, PhD      402 250 3738    davidkay@qwest.net

California
      University of California, San Diego, La Jolla,  California,  92093-0960,  United States; Recruiting
Texas
      M. D. Anderson Cancer Center, Houston,  Texas,  77030,  United States; Recruiting

Study chairs or principal investigators

Jorge E Cortes, MD,  Principal Investigator,  University of Texas M.D. Anderson Cancer Center   
Edward D. Ball, MD,  Principal Investigator,  University of California, San Diego   

Study ID Numbers:  ELP1001; 2003-0475 (MD Anderson)
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  December 19, 2003
ClinicalTrials.gov Identifier:  NCT00074737
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08