Clinical trial NCT00768339: A Phase 1-2, Multicenter, Open-Label Study of AEG35156 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia and Indolent B-Cell Lymphomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Keywords: antisense
AEG35156
lymphocytic
lymphoma
leukemia
B-cell
Lead sponsor: Aegera Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2008-10-08
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 disease. This trial is designed to determine the recommended dose of AEG35156 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and indolent B-cell lymphomas.

Detailed description: 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 disease.

Eligibility criteria: 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 lesions
* 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 therapy
* 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

Primary outcomes:
measure: Objective tumor response according to CLL NCI-WG criteria
timeFrame: Every numbered cycles
Secondary outcomes:
Other outcomes:
Locations:
city: Burbank
country: United States
facility: Providence Saint-Joseph Medical Center
state: California
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic, Taussig Cancer Institute
state: Ohio
city: Temple
country: United States
facility: Scott and White Memorial Hospital
state: Texas
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital - Sir Mortimer B. Davis
state: Quebec
Study officials:
affiliation: The Cleveland Clinic
name: John Sweetenham, MD
role: PRINCIPAL_INVESTIGATOR
References: