Dosing Study of Ara-C/EL625/Idarubicin in Refractory and Relapsed AML

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eleos, Inc.
ClinicalTrials.gov Identifier:
NCT00074737
First received: December 19, 2003
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

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

Cenersen sodium 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 Intervention Phase
Acute Myelogenous Leukemia
Drug: cenersen
Drug: Idarubicin
Drug: Cytarabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open Label, Phase II Dosing Study of Ara-C Chemotherapy in Combination With EL625 and Idarubicin in Refractory and Relapsed Acute Myelogenous Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by Eleos, Inc.:

Primary Outcome Measures:
  • Determine the effective dose of Cytarabine chemotherapy to be used in combination with EL625 and Idarubicin. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Cenersen plus standard of care


Secondary Outcome Measures:
  • Determine the safety profile for the combination of EL625 and Idarubicin +/- Cytarabine. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Standard of care plus cenersen

  • Determine the Complete Response Rate and Time to Progression. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Standard of care plus cenersen


Enrollment: 53
Study Start Date: April 2004
Study Completion Date: May 2007
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: cenersen, idarubicin
cenersen, idarubicin, no cytarabine
Drug: cenersen
cenersen with standard of care
Other Names:
  • cenersen sodium
  • Ol(1)p53
  • EL625
  • Aezea
Drug: Idarubicin
standard of care for AML
Other Name: idamycin
Active Comparator: cenersen, idarubicin, cytarabine
cenersen, idarubicin, standard dose cytarabine
Drug: cenersen
cenersen with standard of care
Other Names:
  • cenersen sodium
  • Ol(1)p53
  • EL625
  • Aezea
Drug: Idarubicin
standard of care for AML
Other Name: idamycin
Drug: Cytarabine
standard of care Ara-C and High dose Ara-C
Other Names:
  • Ara-C
  • HDAC
Active Comparator: cenersen, idarubicin, HDAC
cenersen, idarubicin, HDAC (high dose cytarabine)
Drug: cenersen
cenersen with standard of care
Other Names:
  • cenersen sodium
  • Ol(1)p53
  • EL625
  • Aezea
Drug: Idarubicin
standard of care for AML
Other Name: idamycin
Drug: Cytarabine
standard of care Ara-C and High dose Ara-C
Other Names:
  • Ara-C
  • HDAC

Detailed Description:

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 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 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 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

Prohibited Medications during the first week of each course:

  • Acetaminophen
  • Hi-Dose antioxidants (e.g., Vitamins C, E; Multivitamins)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00074737

Locations
United States, California
University of California, San Diego
La Jolla, California, United States, 92093-0960
United States, Florida
University of Miami Health Center
Miami, Florida, United States, 33136
United States, Missouri
Washington University Medical Center (Siteman Cancer Center)
St. Louis, Missouri, United States, 63110
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
North Shore University Hospital
Lake Success, New York, United States, 11041
United States, Texas
M. D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Eleos, Inc.
Investigators
Principal Investigator: Jorge E Cortes, MD M.D. Anderson Cancer Center
Principal Investigator: Edward D. Ball, MD University of California, San Diego
Principal Investigator: John DiPersio, MD Washington University Medical Center, Siteman Cancer Center
Principal Investigator: Maria Baer Roswell Park Cancer Institute
Principal Investigator: Jonathan Kolitz, MD, FACP North Shore University Hospital
Principal Investigator: Hugo Fernandez, MD University of Miami
  More Information

Additional Information:
No publications provided

Responsible Party: Eleos, Inc.
ClinicalTrials.gov Identifier: NCT00074737     History of Changes
Other Study ID Numbers: ELP1001, 2003-0475 (MD Anderson)
Study First Received: December 19, 2003
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Eleos, Inc.:
Refractory or Relapsed Acute Myelogenous Leukemia (AML)
Antisense

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014