Clinical trial NCT00321724: AZD2171 in Treating Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia
Official title: A Phase II Trial of AZD2171 in Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: B-cell Chronic Lymphocytic Leukemia
Refractory Chronic Lymphocytic Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-05-04
Enrollment: 35
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: This phase II trial is studying how well AZD2171 works in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia. AZD2171 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer cells

Detailed description: OBJECTIVES:

I. Evaluate the response rate in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL) treated with AZD2171.

II. Evaluate the toxicity of AZD2171 in patients with relapsed or refractory B-CLL.

III. Evaluate the complete response rate, progression-free and overall survival distributions, and duration of response in patients with relapsed or refractory B-CLL treated with AZD2171.

IV. Assess vascular endothelial growth factor receptor-2 (VEGFR-2) protein and phosphorylation levels in B-CLL cells using pretreatment samples and evaluate the association between Rai stage at study entry and clinical response to AZD2171.

V. Perform preclinical testing of AZD2171 in the induction of B-CLL cell apoptosis/cell death using pretreatment samples, and evaluate the ability to downregulate the phosphorylation status of VEGFR-2 of B-CLL cells by comparing in vitro samples with and without AZD2171.

VI. Study the differences in in vitro levels of B-CLL cell apoptosis/cell death and alteration of VEGFR-2 phosphorylation using pretreatment samples with and without AZD2171 and how these differences correlate with clinical outcomes.

VII. Assess if the clinical responses are associated with changes in bone marrow vascularity.

OUTLINE: This is a multicenter study.

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sampling and biopsies at baseline and periodically throughout study for biomarker and correlative studies.

After completion of study therapy, patients are followed periodically for up to 5 years from study entry.

Eligibility criteria: Inclusion Criteria:

* Histological confirmation of B-cell chronic lymphocytic leukemia (B-CLL)

  * Peripheral blood lymphocyte count \> 5,000/mm³
  * Small to moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes
  * Bone marrow aspirate with ≥ 30% lymphoid cells
  * Monoclonality of B lymphocytes by immunophenotyping, demonstrating all of the following:

    * B-cell markers with CD5 antigen in the absence of other pan-T-cell markers (CD3, CD2, etc.)
    * CD19 and/or CD20
    * Expression of CD23 on the CLL cells OR dim B-cell expression of kappa or lambda light chains
* Disease must be refractory to or progressive after treatment with at least 1 course containing a purine nucleoside analog (e.g., fludarabine, cladribine, or pentostatin)
* Life expectancy \> 6 months
* ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
* Absolute neutrophil count ≥ 1,500/mm³
* Platelet count ≥ 50,000/mm³
* Hemoglobin ≥ 8 g/dL
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)

  * Patients with Gilbert's syndrome may have a bilirubin ≥ 1.5 times ULN
* AST and ALT ≤ 2.5 times ULN
* Creatinine ≤ 1.5 times ULN
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No history of allergies to compounds similar to AZD2171
* QTc prolongation \< 500 msec
* No other significant ECG abnormality
* No history of familial long QT syndrome
* Proteinuria \< 1+ by dipstick OR protein \< 1 g/24 hr urine collection
* No known HIV positivity
* No New York Heart Association (NYHA) class III or IV disease

  * NYHA class II disease controlled with treatment and monitoring allowed
* No other uncontrolled illness including, but not limited to, the following:

  * Hypertension
  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Psychiatric illness or social situations that would limit compliance
* See Disease Characteristics
* More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, anti-vascular endothelial growth factor (VEGF) treatment, or major surgery and recovered
* More than 30 days since prior investigational agents
* No concurrent drugs or biologics with proarrhythmic potential
* No other concurrent investigational agents
* No other concurrent anticancer therapy

Primary outcomes:
measure: Confirmed response defined to be an objective status of complete remission [CR], nodular partial remission [nPR], and partial remission [PR]
timeFrame: Up to 5 years
Secondary outcomes:
measure: Complete response rate estimated by the number of confirmed complete responses (CR) observed in the trial divided by the total number of evaluable patients
timeFrame: Up to 5 years
measure: Overall survival
timeFrame: From the date of registration to the date of death, assessed up to 5 years
measure: Time to progression as estimated by Kaplan-Meier method
timeFrame: From the date of registration to the date of disease progression, assessed up to 5 years
measure: Duration of response
timeFrame: From the date at which the patient's objective status is first noted to be a response to the date that progression or death is documented, assessed up to 5 years
Other outcomes:
Locations:
city: Rochester
country: United States
facility: North Central Cancer Treatment Group
state: Minnesota
Study officials:
affiliation: North Central Cancer Treatment Group
name: Neil Kay
role: PRINCIPAL_INVESTIGATOR
References: