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AEG35156-204: A Phase 1-2, Multicenter, Open-Label Study of the X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia and Indolent B-Cell Lymphomas

Phase 1/Phase 2
18 Years
Not Enrolling
Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell

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Trial Information

AEG35156-204: A Phase 1-2, Multicenter, Open-Label Study of the X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia and Indolent B-Cell Lymphomas

Apoptotic induction in cancer cells is a sought after therapeutic goal. Most successful
anticancer agents activate apoptosis pathways in the cancers they treat. Apoptotic pathways
in cells appear to converge on a single family of enzymes, the caspases, which are proteases
that dismantle the cell in an orderly, non-inflammatory fashion, resulting in cell death.
The X-linked Inhibitor of Apoptosis (XIAP) is the only known cellular inhibitor of caspases,
its over expression thereby blocking the principal means of apoptosis. A wide range of
evidence indicates that cellular overexpression of members of the IAP family is a
fundamental means by which many cancer cells evade death, even in the presence of strong
extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) apoptotic cues.
The inhibition of cellular XIAP activity, specifically in cancer cells under stress and
primed for apoptosis by chemotherapeutic agents, is viewed as a powerful means of tipping
the balance towards cell death. In particular, XIAP has been shown to be overexpressed in
lymphoma. AEG35156 is a second generation antisense which targets XIAP mRNA to lower XIAP
levels and the apoptotic threshold of cancer cells, enhancing their sensitivity to intrinsic
death and chemotherapy. AEG35156 has shown early evidence of activity in patients with
advanced indolent B-cell lymphomas in Phase 1 trials and merits further evaluation in this

Inclusion Criteria:

- Patients with an histologically confirmed diagnosis of CLL as per NCI-WG criteria or

- Patients with an histologically confirmed diagnosis of one of the following indolent
B-cell lymphomas: (Follicular lymphoma (FL); Small lymphocytic lymphoma (SLL);
Marginal zone lymphoma; Lymphoplasmacytic lymphoma)

- Relapsed or refractory patients who have failed at least 2 prior lines of therapy,
one of which may have been high dose therapy and autologous stem cell
transplantation. Steroids alone when used for autoimmune phenomena do not qualify as
prior therapy

- ECOG performance less or equal than 2

- Life expectancy of at least 3 months

- Age greater or equal than 18 years

- Signed, written IRB-approved informed consent

- A negative serum pregnancy test (if applicable)

- Acceptable liver function:(Bilirubin within normal limit; AST (SGOT) and ALT (SGPT)
less or equal than 2.5 x ULN or less or equal than 5 x ULN if there are liver
lymphomatous involvement)

- Acceptable renal function: (Serum creatinine within normal limits, OR calculated
creatinine clearance greater or equal than 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal)

- Acceptable hematologic status: (Granulocyte greater or equal than 1000 cells/uL;
Platelet count greater or equal than 50,000 /uL)

- Acceptable coagulation status:(PT within normal limits; PTT within normal limits)

- For women of child-producing potential, the use of effective contraceptive methods
during the study

- Prior radiotherapy for local disease is allowed provided disease progression has been
documented, and treatment completed at least 4 weeks prior to registration

Exclusion Criteria:

- Uncontrolled autoimmune hemolysis and/or thrombocytopenia

- Richter's transformation

- Histologic transformation

- Patients with peripheral neuropathy

- Active progressive leptomeningeal disease including the presence of any related
symptoms or need for corticosteroids. A CT or MRI scan of the head is necessary in
patients with a history of leptomeningeal disease to document the stability of prior

- Pregnant or nursing women. NOTE: Women of child-bearing potential must agree to use
adequate contraception (sterile or surgically sterile; hormonal or barrier method of
birth control; or abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Men who are unwilling to use acceptable forms of birth control when engaging in
sexual contact with women of child bearing potential

- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic

- Known infection with HIV, hepatitis B, or hepatitis C

- Serious nonmalignant disease that could compromise protocol objectives in the opinion
of the investigator and/or the sponsor

- Patients who are currently receiving any other investigational agent. Subjects who
have used a previous antisense oligonucleotide in the last 90 days will be excluded

- Unwillingness or inability to comply with procedures required in this protocol

Type of Study:


Study Design:

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

Outcome Measure:

Objective tumor response according to CLL NCI-WG criteria

Outcome Time Frame:

Every numbered cycles

Safety Issue:


Principal Investigator

John Sweetenham, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Cleveland Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

September 2008

Completion Date:

September 2011

Related Keywords:

  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma, B-Cell
  • antisense
  • AEG35156
  • lymphocytic
  • lymphoma
  • leukemia
  • B-cell
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, B-Cell



New York Medical College Valhalla, New York  10595
Scott and White Memorial Hospital Temple, Texas  76508
Providence Saint-Joseph Medical Center Burbank, California  91505
The Cleveland Clinic, Taussig Cancer Institute Cleveland, Ohio  44195